Pyrazole derivatives

ABSTRACT

A compound of the formula (I):  
                 
 
     wherein R 1  is hydrogen or lower alkyl;  
     R 2  is lower alkyl, etc.;  
     R 3  is lower alkoxy, etc.;  
     R 4  is hydroxy, etc.;  
     X is O, S, etc.;  
     Y is CH or N;  
     Z is lower alkylene or lower alkenylene; and  
     m is 0 or 1; or salts thereof, which are useful as a medicament.

TECHNICAL FIELD

[0001] This invention relates to pyrazole compounds havingpharmacological activity, to a process for their production and to apharmaceutical composition containing the same.

BACKGROUND ART

[0002] The presence of two cyclooxygenase isoenzymes, cyclooxygenase-I(COX-I) andcyclooxygenase-II (COX-II) is known (Proc. Nat. Acad. Sci.USA 88, 2692-2696 (1991)).

[0003] Traditional non steroidal anti-inflammatory compounds (NSAIDs)have inhibiting activities of both COX-I and COX-II (J. Biol. Chem.,268, 6610-6614 (1993), etc). The therapeutic use thereof involvesundesired effects on the gastrointestinal tract, such as bleeding,erosions, gastric and intestinal ulcers, etc.

[0004] It was reported that selective inhibition of COX-II showsanti-inflammatory and analgesic activities comparable with conventionalNSAIDs but with a lower incidence of some gastrointestinal undesiredeffects (Pro. Nat. Acad. Sci. USA, 91, 3228-3232(1994)). Accordingly,various selective COX-II inhibitors have been prepared. However, it wasreported that those “selective COX-II inhibitor” show some side-effectson kidney and/or insufficient efficacy on acute pains.

[0005] Further, some compounds such as SC-560, mofezolac, etc, whichhave certain selective inhibiting activity against COX-I. W098/57910shows some compounds having such activity. However, their selectivity ofinhibiting COX-I does not seem to be enough to use them as a clinicallyacceptable and satisfactory analgesic agent due to theirgastrointestinal disorders.

[0006] W002/055502 shows some pyridine derivatives having cyclooxygenaseinhibiting activity, particularly cyclooxygenase-I inhibiting activity.Further, W003/040110 shows some triazole derivatives havingcyclooxygenase inhibiting activity, particularly cyclooxygenase-Iinhibiting activity. And W099/51580 shows some triazole derivativeshaving an inhibiting activity of cytokine production.

DISCLOSURE OF INVENTION

[0007] This invention relates to pyrazole compounds, which havepharmacological activity such as cyclooxygenase (hereinafter describedas COX) inhibiting activity, to a process for their production, to apharmaceutical composition containing the same and to a use thereof.

[0008] Accordingly, one object of this invention is to provide thepyrazole compounds, which have a COX inhibiting activity.

[0009] Another object of this invention is to provide a process forproduction of the pyrazole compounds.

[0010] A further object of this invention is to provide a pharmaceuticalcomposition containing, as active ingredients, the pyrazole compounds.

[0011] Still further object of this invention is to provide a use of thepyrazole compounds for manufacturing a medicament for treating orpreventing various diseases.

[0012] The new pyrazole compounds of this invention can be representedby the following general formula (I):

[0013] wherein R¹ is hydrogen or lower alkyl;

[0014] R² is lower alkyl optionally substituted with halogen, hydroxy,lower alkoxyimino or lower alkoxy; lower alkenyl; cycloalkyl; cyano;lower alkanoyl; cycloalkylcarbonyl; N,N-di(lower)alkylcarbamoyl;carbamoyl; N-lower alkoxy-N-lower alkylcarbamoyl; amino;di(lower)alkylamino; lower alkoxycarbonylamino;N,N-di(lower)alkylcarbamoylamino;N-(N,N-di(lower)alkylcarbamoyl)-N-lower alkylamino; halogen; hydroxy;carboxy; lower alkoxycarbonyl; aroyl; heterocycliccarbonyl; heterocyclicgroup; lower alkylsulfonyl; lower alkoxy optionally substituted withlower alkoxy, N,N-di(lower)alkylcarbamoyl or halogen; cycloalkyloxy;lower alkylthio; or lower alkylsufinyl;

[0015] R³is lower alkyl optionally substituted with amino,carbamoylamino or lower alkylsulfonylamino; halogen; cyano; hydroxy;lower alkanoyloxy; lower alkylenedioxy; lower alkoxy optionallysubstituted with aryl, hydroxy, cyano, amino, lower alkoxycarbonylamino,lower alkylsulfonylamino or carbamoylamino; nitro; amino; hetrocyclicgroup; lower alkylthio; lower alkylsulfinyl; or lower alkylsufonyl;

[0016] R⁴ is hydrogen; cyano; amino optionally substituted withphthaloyl or lower alkyl; aryl; heterocyclic group; lower alkoxy;hydroxy; lower alkylsulfonyloxy; lower alkanoyloxy; lower alkylsubstituted with tritylamino and lower alkoxycarbonyl, amino and loweralkoxycarbonyl, amino and carboxy, amino and carbamoyl, or amino andhydroxy; N-lower alkoxycarbonyl-N-lower alkylamino; lower alkanoyloptionally substituted with halogen; carboxy; lower alkylsulfonyl;sulfo; lower alkylsilyloxy; lower alkoxycarbonyl; sulfamoyl optionallysubstituted with lower alkyl; carbamoyl optionally substituted withlower alkyl; lower alkylthio; lower alkylsulfinyl; carbamoyloxy;thioureido; or a group of the formula:

R⁵-G-J-

[0017] in which G is -CO- or -SO₂-;

J is -N(R⁶)-

[0018] (wherein R⁶ is hydrogen or lower alkyl); and

[0019] R⁵ is amino optionally substituted with lower alkoxycarbonyl orlower alkyl; lower alkyl optionally substituted with hydroxy, loweralkoxycarbonylamino, lower alkanoyloxy, amino or halogen; lower alkoxy;hydrogen; heterocyclic group; or aryl;

[0020] X is O, S, SO or SO₂;

[0021] Y is CH or N;

[0022] Z is lower alkylene or lower alkenylene; and

[0023] m is 0 or 1;

[0024] provided that when R⁴ is hydrogen;

[0025] then R³ is lower alkyl substituted with amino, carbamoylamino orlower alkylsulfonylamino; or lower alkoxy substituted with aryl,hydroxy, cyano, amino, lower alkoxycarbonylamino, loweralkylsulfonylamino or carbamoylamino; or salts thereof.

[0026] The object compound (I) of the present invention can be preparedby the following processes.

[0027] In the above processes, R¹, R², R³, R⁴, X, Y, Z and m are each asdefined above,

[0028] Xa is O or S, and

[0029] Q is hyroxy or an acid residue.

[0030] The compounds of formula (I) may contain one or more asymmetriccenters and thus they can exist as enantiomers or diastereoisomers. Thisinvention includes both mixtures and separate individual isomers.

[0031] The compounds of the formula (I) may also exist in tautomericforms and the invention includes both mixtures and separate individualtautomers.

[0032] The compounds of the formula (I) and its salts can be in a formof a solvate, which is included within the scope of the presentinvention. The solvate preferably include a hydrate and an ethanolate.

[0033] Also included in the scope of invention are radiolabelledderivatives of compounds of formula (I) which are suitable forbiological studies.

[0034] In the above and subsequent description of the presentspecification, suitable examples of the various definitions to beincluded within the scope of the invention are explained in detail inthe following.

[0035] The term “lower” is intended to mean a group having 1 to 6 carbonatom(s), unless otherwise provided.

[0036] So, the “lower alkyl” and lower alkyl moiety in the terms “loweralkylthio”, “lower aklylsufinyl”, “lower alkylsulfonyl” and “loweralkylsulfonylamino” means a straight or branched chain aliphatichydrocarbon, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, isoamyl, hexyl, and the like, and it is preferably(C₁-C₄)alkyl, more preferably (C₁-C₂)alkyl, most preferably methyl.

[0037] The “halogen” may include a fluorine atom, a chlorine atom, abromine atom and an iodine atom, and it is preferably a fluorine atom ora chlorine atom, more preferably a chlorine atom.

[0038] The “lower alkyl substituted with halogen” means a monovalentgroup in which the above lower alkyl is substituted by one or more (morepreferably 1 to 5, most preferably 1 to 3) above halogen atom(s), suchas fluoromethyl, chloromethyl, difluoromethyl, dichloro-methyl,dibromomethyl, trifluoromethyl, trichloromethyl, fluoroethyl,chloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl,2,2,3,3,3-pentafluoroethyl, fluoropropyl, fluorobutyl, fluorohexyl, orthe like, and it is preferably (C₁-C₄)alkyl substituted with halogen,more preferably (C₁-C₂) alkyl substituted with halogen, more preferably(C₁-C₂)alkyl substituted with fluorine, more preferably methylsubstituted with fluorine, most preferably difluoromethyl ortrifluoromethyl.

[0039] The “lower alkyl substituted with hydroxy” means a monovalentgroup in which the above lower alkyl is substituted by a OH group, suchas hydroxymethyl, hydroxyethyl, hydroxypropyl, 1-hydroxyisopropyl,2-hydroxyisopropyl, hydroxybutyl, hydroxyisobutyl, hydroxy-tert-butyl,hydroxyhexyl, or the like, and it is preferably (C₁-C₄)alkyl substitutedwith hydroxy, more preferably (C₁-C₃)alkyl substituted with hydroxy.

[0040] The “lower alkenyl” means a straight or branched chain aliphatichydrocarbon having more than one double bond between two carbon atom,such as ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl,hexenyl, and the like, and it is preferably (C₂-C₄)alkenyl, morepreferably (C₂-C₃)alkenyl.

[0041] The “lower alkoxy” means a straight or branched chain aliphatichydrocarbon oxy group, such as methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy, tert-butoxy, pentoxy, hexoxy, or the like, and it ispreferably (C₁-C₄)alkoxy, more preferably (C₁-C₂)alkoxy, most preferablymethoxy.

[0042] The “cycloalkyl” and cycloalky moiety in the terms“cycloalkylcarbonyl” and “cycloalkyloxy” means C₃-C₁₀ cycloalkyl group,such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,norbornyl, adamantyl, and the like, and it is preferably C₃-C₆cycloalkyl, more preferably C₃-C₅ cycloalkyl, most preferablycyclopropyl or cyclopentyl.

[0043] The “di(lower)alkylamino” means a amino group substituted by thesame or different above (lower)alkyl groups, such as dimethylamino,diethylamino, dipropylamino, diisopropylamino, dibutylamino,diisobutylamino, dipentylamino, dihexylamino, ethylmethylamino,methylpropylamino, butylmethylamino, ethylpropylamino, butylethylamino,or the like, and it is preferably [di(C₁-C₄)alkyl]amino, more preferably[di(C₁-C₄)alkyl]amino, most preferably dimethylamino.

[0044] The “lower alkoxycarbonyl” and lower alkoxycarbonyl moiety in theterm “lower alkoxycarbonylamino” means a -CO₂-[(lower)alkyl] group, suchas methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl,hexoxycarbonyl, and the like, and it is preferably[(C₁-C4)alkoxy]carbonyl, more preferably ethoxycarbonyl ortert-butoxycarbonyl.

[0045] The “lower alkanoyl” means carbonyl group which is substituted byhydrogen or the above (lower)alkyl groups, such as formyl, acetyl,propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl,2,2-dimethylpropanoyl, hexanoyl, or the like, and it is preferably(C₁-C₅)alkanoyl, more preferably (C₂-C₃)alkanoyl, most preferablyacetyl.

[0046] The “cycloalkylcarbonyl” means a carbonyl group substituted withcycloalkyl group mentioned above, such as cyclopropylcarbonyl,cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl,cycloheptylcarbonyl, norbornylcarbonyl, adamantylcarbonyl, and the like,and it is preferably [(C₃-C₆) cycloalkyl]carbonyl, more preferably[(C₃-C₅) cycloalkyl]carbonyl, most preferably cyclopropylcarbonyl.

[0047] The “N,N-di(lower)alkylcarbamoyl” and N,N-di(lower)alkylcarbamoylmoiety in the term “N,N-di(lower)alkylcarbamoylamino” means a carbamonylgroup substituted with the same or different lower alkyl groupsmentioned above, such as dimethylcarbamoyl, diethylcarbamoyl,dipropylcarbamoyl, diisopropylcarbamoyl, dibutylcarbamoyl,diisobutylcarbamoyl, dipentylcarbamoyl, dihexylcarbamoyl,ethylmethylcarbamoyl, methylpropylcarbamoyl, butylmethylcarbamoyl,ethylpropylcarbamoyl, butylethylcarbamoyl, and the like, and it ispreferably [di(C₁-C₄)alkyl]carbamoyl, more preferably[di(C₁-C₂)alkyl]carbamoyl, most preferably dimethycarbamoyl orethylmethylcarbamoyl.

[0048] The “lower alkoxy substituted with halogen” means a monovalentgroup in which the above lower alkoxy is substituted by one or more(more preferably 1 to 5, most preferably 1 to 3) above halogen atom(s),such as fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy,dibromomethoxy, trifluoromethoxy, trichloromethoxy, fluoroethoxy,chloroethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy,2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy,2,2,3,3,3-pentafluoroethoxy, fluoropropoxy, fluorobutoxy,fluorohexyloxy, or the like, and it is preferably (C₁-C₄)alkoxysubstituted with halogen, more preferably (C₁-C₂)alkoxy substituted.with halogen, more preferably (C₁-C₂)alkoxy substituted with fluorine,more preferably ethoxy substituted with fluorine, most preferably2,2-difluoroethoxy.

[0049] The “lower alkyl substituted with amino” means a monovalent groupin which the above lower alkyl is substituted by a amino group, such asaminomethyl, 2-aminoethyl, aminopropyl, 1-aminoisopropyl,2-aminoisopropyl, aminobutyl, aminoisobutyl, amino-tert-butyl,aminohexyl, or the like, and it is preferably (C₁-C₄)alkyl substitutedwith amino, more preferably (C₁-C₂)alkyl substituted with amino.

[0050] The “lower alkyl substituted with carbamoylamino” means amonovalent group in which the above (lower)alkyl is substituted by acarbamoylamino group (urea group), such as carbamoylaminomethyl,2-(carbamoylamino)ethyl, carbamoylaminopropyl,1-(carbamoylamino)isopropyl, 2-(carbamoylamino)isopropyl,carbamoylaminobutyl, carbamoylaminoisobutyl, carbamoylamino-tert-butyl,carbamoylaminohexyl, or the like, and it is preferably (C₁-C₄)alkylsubstituted with carbamoylamino, more preferably (C₁-C₂)alkylsubstituted with carbamoylamino.

[0051] The “aryl” and ar moiety in the term “aroyl” means an aromatichydrocarbon group, such as phenyl, naphtyl, indenyl, or the like, and itis preferably (C₆-C₁₀)aryl, more preferably phenyl.

[0052] The “aroyl” means a carbonyl group substituted with aryl groupmentioned above, such as benzoyl, naphthoyl, or the like, and it ispreferably benzoyol.

[0053] The “lower alkanoyloxy” means a monovalent group in which oxygenatom is substituted with lower alkanoyl group mentioned above, such asformyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl,2,2-dimethylpropanoyl, hexanoyl, or the like, and it is preferably[(C₁-C₄)alkanoyl]oxy, more preferably [(C₁-C₂)alkanoyl]oxy, mostpreferably acetoxy.

[0054] The “lower alkylene” means a straight or branched chain aliphatichydrocarbon divalent group, such as methylene, ethylene,1-methylethylene, 2-methylethylene, propylene, methylpropylene,butylene, pentylene, hexylene, and the like, and it is preferably(C₁-C₄) alkylene, more preferably (C₁-C₂)alkylene.

[0055] The “lower alkylenedioxy” means -O-[(lower)alkylene]-O- group.That is, in this case, R³ is divalent group and is also substituted atthe next carbon atom. This group may be exemplified by methylenedioxy,ethylenedioxy, methylethylenedioxy, propylenedioxy, and the like, and itis preferably [(C₁-C₄)alkylene]dioxy, more preferably [(C₁-C₂)alkylene]dioxy, most preferably methylenedioxy.

[0056] The “lower alkoxy substituted with aryl” means a monovalent groupin which the above lower alkoxy. is substituted by aryl group mentionedabove. The “lower alkoxy substituted with hydroxy” means a monovalentgroup in which the above lower alkoxy is substituted by hydroxy.

[0057] The “lower alkoxy substituted with cyano” means a monovalentgroup in which the above (lower)alkoxy is substituted by a cyano group,such as cyanomethoxy, cyanoethoxy, cyanopropoxy, cyanobutoxy, and thelike, and it is preferably (C1-C4) alkoxy substituted with cyano, morepreferably (C1-C2)alkoxy substituted with cyano, most preferablycyanomethoxy.

[0058] The “lower alkoxy substituted with amino” means a monovalentgroup in which the above lower alkoxy is substituted with amino.

[0059] The “lower alkoxy” substituted with lower alkoxycarbonylaminomeans a lower alkoxy substituted with amino group mentioned abovesubstituted with lower alkoxycarbonyl group mentioned above.

[0060] The “lower alkoxy” substituted with lower alkylsulfonylaminomeans a monovalent group in which the above lower alkoxy is substitutedwith lower alkylsulfonylamino group mentioned above.

[0061] The “lower alkoxy substituted with carbamoylamino” means amonovalent group in which the above lower alkoxy is substituted by a(carbamoyl)amino (urea) group, such as [(carbamoyl)amino]methoxy,[(carbamoyl)amino]ethoxy, [(carbamoyl)amino]propoxy,[(carbamoyl)amino]cyanobutoxy, and the like, and it is preferably(C1-C4)alkoxy substituted with [(carbamoyl)amino], more preferably(C₁-C₂)alkoxy substituted with [(carbamoyl)amino], most preferablycarbamoylaminomethoxy.

[0062] The “lower alkokycarbonylamino” means an amino group substitutedwith lower alkokycarbonyl group mentioned above.

[0063] The “lower alkylsulfonylamino” means a sulfonylamino groupsubstituted with lower alkyl group mentioned above.

[0064] Suitable “heterocyclic group” may be one containing at least onehetero atom selected from nitrogen, sulfur and oxygen atom, and mayinclude saturated or unsaturated, monocyclic or polycyclic heterocyclicgroup, and preferable heterocyclic group may be N-containingheterocyclic group such as unsaturated 3 to 6-membered heteromonocyclicgroup containing 1 to 4 nitrogen atoms, for example, pyrrolyl,pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazolyl [e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,2H-1,2,3-triazolyl, etc.], tetrazolyl [e.g. 1H-tetrazolyl,2H-tetrazolyl, etc.], etc.; saturated 3 to 7-membered heteromonocyclicgroup containing 1 to 4 nitrogen atoms [e.g. pyrrolidinyl,imidazolidinyl, piperidyl, piperazinyl, homopiperazinyl, etc.];

[0065] unsaturated condensed heterocyclic group containing 1 to 5nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl,benzimidazolyl, quinolyl, isoquinolyl, imidazopyridyl, indazolyl,benzotriazolyl, tetrazolopyridazinyl [e.g. tetrazolo[1,5-b]pyridazinyl,etc.], quioxalinyl, etc.;

[0066] unsaturated 3 to 6-membered heteromonocyclic group containing anoxygen atom, for example, pyranyl, furyl, etc.;

[0067] saturated 3 to 6-membered heteromonocyclic group containing anoxygen atom, for example, 1H-tetrahydropyranyl, tetrahydrofuranyl, etc.;

[0068] unsaturated 3 to 6-membered heteromonocyclic group containing 1to 2 sulfur atoms, for example, thienyl, etc.;

[0069] unsaturated 3 to 6-membered heteromonocyclic group containing 1to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl,isoxazolyl, oxadiazolyl [e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl, etc.], oxazolinyl [e.g. 2-oxazolinyl, etc.], etc.;

[0070] saturated 3 to 6-membered heteromonocyclic group containing 1 to2 oxygen atoms and 1 to 3 nitrogen atoms [e.g. morpholinyl, etc.];

[0071] unsaturated condensed heterocyclic group containing 1 to 2 oxygenatoms and 1 to 3 nitrogen atoms [e.g. benzofurazanyl, benzoxazolyl,benzoxadiazolyl, etc.];

[0072] unsaturated 3 to 6-membered heteromonocyclic group containing 1to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl [e.g. 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, etc.], etc.;

[0073] saturated 3 to 6-membered heteromonocyclic group containing 1 to2 sulfur atoms and 1 to 3 nitrogen atoms [e.g. thiazolidinyl, etc.];

[0074] unsaturated condensed heterocyclic group containing 1 to 2 sulfuratoms and 1 to 3 nitrogen atoms [e.g. benzothiazolyl, benzothiadiazolyl,etc.];

[0075] unsaturated condensed heterocyclic group containing 1 to 2 oxygenatoms [e.g. benzofuranyl, benzodioxolyl, chromanyl, etc.] and the like.

[0076] Said “heterocyclic group” may be substituted with lower alkyl asexemplified above or oxo, in which preferable one is pieridyl, pyrrolyl, 3-metyl-1,2,4-oxadiazol-5-yl, isoindole-1,3-dione-2-yl or1-methyl-H-imidazolyl.

[0077] The heterocyclic moiety in the term “heterocycliccarbonyl” meansheterocyclic group mentioned above and, it is preferably piperidyl.

[0078] The “lower alkylsulfonyloxy” means a sulfonyloxy groupsubstituted with lower alkyl group mentioned above.

[0079] The “lower alkanoyl substituted with halogen” means a loweralkanoyl group mentioned above substituted with halogen mentioned above,such as trifluoroacetyl, and the like.

[0080] The “lower alkylsilyloxy” means silyloxy group substituted by thesame or different above (lower)alkyl groups, such as trimethylsilyloxy,triethylsilyloxy, tert-butyldimethylsilyloxy, or the like, and it ispreferably tert-butyldimethylsilyloxy.

[0081] The “acid residue” means halogen (e.g. fluoro, chloro, bromo,iodo), arenesulfonyloxy (e.g. benzenesulfonyloxy, tosyloxy, etc.),alkanesulfonyloxy (e.g. mesyloxy, ethanesulfonyloxy, etc.), and thelike.

[0082] Preferred compound (I) is one having hydrogen for R¹; lower alkyloptionally substituted with halogen; cycloalkyl; halogen; or loweralkoxy optionally substituted with halogen for R²; lower alkoxy for R³;R⁵-G-J-(wherein -CO- or -SO2- for G, -NH- for J, amino or lower alkylfor R⁵) for R⁴; O for X; CH or N for Y; lower alkylene for Z; and 0 or 1for m.

[0083] Suitable salts of the compounds (I) are pharmaceuticallyacceptable conventional non-toxic salts and include a metal salt such asan alkali metal salt (e.g., sodium salt, potassium salt, etc.) and analkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), anammonium salt, an organic base salt (e.g., trimethylamine salt,triethylamine salt, pyridine salt, picoline salt, dicyclohexylaminesalt, etc.), an organic acid salt (e.g., acetate, maleate, tartrate,methanesulfonate, benzenesulfonate, formate, toluenesulfonate,trifluoroacetate, etc.), an inorganic acid salt (e.g., hydrochloride,hydrobromide, sulfate, phosphate, etc.), a salt with an amino acid(e.g., arginine, aspartic acid, glutamic acid, etc.), or the like.

[0084] The processes for preparing the object compounds are explained indetail in the following.

[0085] Process (1)

[0086] The object compound (Ia) or its salt can be prepared byreactingacompound (II) or its salt with a compound (III) or its salt in theacidic condition, for example, by using acetic acid.

[0087] Suitable salts of the compounds (Ia) and (III) may be the same asthose exemplified for the compound (I).

[0088] Suitable salt of the compound (II) may be acid addition saltexemplified for the compound (I).

[0089] The reaction is carried out in a conventional solvent such aswater, an alcohol (e.g. methanol, ethanol, propanol, isopropanol, etc.),tetrahydrofuran, dioxane, etc. or a mixture of thereof.

[0090] The reaction temperature is not critical and the reaction isusually carried out under cooling to heating.

[0091] According to the starting material, the heterocyclic ring isformed but not to form pyrazole ring. In this case, the dehydrationprocess is need to form pyrazole ring.

[0092] The hydration process is carried out under the highertemperature.

[0093] Process (2)

[0094] The object compound (Ib) or its salt can be prepared by reactinga compound (IV) or its salt with a compound (V) or its salt.

[0095] Suitable salts of the compounds (Ia), (IV) and (V) may be thesame as those exemplified for the compound (I).

[0096] When the compound (V) having halogen for Q is used in thisreaction, the reaction is preferably carried out in the presence of abase such as alkali metal (e.g. sodium, potassium, etc.), an alkalineearth metal (e.g. magnesium, calcium, etc. ), the hydride or hydroxideor carbonate or bicarbonate thereof.

[0097] When the compound (V) having hydroxy for Q is used in thisreaction, the reaction is preferably carried out in the presence ofdiethyl azodicarboxylate and triphenylphosphine.

[0098] The reaction is usually carried out in a conventional solventwhich does not adversely influence the reaction such as water, dioxane,a alcohol (e.g. methanol, ethanol, etc.), acetonitrile, tetrahydrofuran,acetic acid, N,N-dimethylformamide, or a mixture thereof.

[0099] The reaction temperature is not critical and the reaction can becarried out under cooling to heating.

[0100] In order to illustrate the usefulness of the object compounds(I), the pharmacological test data of the com pounds (I) are shown inthe following.

[A] ANALGESIC ACTIVITY

[0101] Effect on adjuvant arthritis in rats

[0102] (i) Test Method :

[0103] Analgesic activity of a single dose of agents in arthritic ratswas studied.

[0104] Arthritis was induced by injection of 0.5 mg of Mycobacteriumtuberculosis (Difco Laboratories, Detroit, Mich.) in 50 μl of liquidparaffin into the right hind footpad of Lewis rats aged 7 weeks.Arthritic rats were randomized and grouped (n=10) for drug treatmentbased on pain threshold of left hind paws and body weight on day 22.

[0105] Drugs (Test compounds) were administered and the pain thresholdwas measured 2hrs after drug administration. The intensity ofhyperalgesia was assessed by the method of Randall - Selitto. Themechanical pain threshold of the left hind paw (uninjected hind paw) wasdetermined by compressing the ankle joint with a balance pressureapparatus (Ugo Basile Co.Ltd., Varese, Italy). The threshold pressure ofrats squeaking or struggling was expressed in grams. The thresholdpressure of rats treated with drugs was compared with that ofnon-treated rats. A dose showing the ratio of 1.5 is considered to bethe effective dose.

[0106] (ii) Test Results: Test compound Dose The coefficient of (ExampleNo.) (mg/kg) analgesic 23 3.2   >1.5 28 3.2   >1.5 61 3.2   >1.5 1813.2 >=1.5 240 3.2 >=1.5 248 3.2 >=1.5 250 3.2 >=1.5 254 3.2 >=1.5 2673.2 >=1.5

[0107] [B] Inhibiting activity against COX-I and COX-II (Whole BloodAssay):

[0108] (i) Test Method : Whole blood assay for COX-I

[0109] Fresh blood was collected by syringe without anticoagulants fromvolunteers with consent. The subjects had no apparent inflammatoryconditions and had not taken any medication for at least 7 days prior toblood collection.

[0110] 500 μl Aliquots of human whole blood were immediately incubatedwith 2 μl of either dimethyl sulfoxide vehicle or a test compound atfinal concentrations for 1r at 37° C. to allow the blood to clot.Appropriate treatments (no incubation) were used as blanks. At the endof the incubation, 5 μl of 250mM Indomethacin was added to stop thereaction. The blood was centrifuged at 6000 x g for 5min at 4° C. toobtain serum. A 100 μl aliquot of serum was mixed with 400 μl methanolfor protein precipitation. The supernatant was obtained by centrifugingat 6000 x g for Smin at 4° C. and was assayed for TXB₂ using an enzymeimmunoassay kit according to the manufacturer's procedure. For a testcompound, the results were expressed as percent inhibition ofthromboxane B₂(TXB₂) production relative to control incubationscontaining dimethyl sulfoxide vehicle.

[0111] The data were analyzed by that a test compound at the indicatedconcentrations was changed log value and was applied simple linearregression. IC₅₀ value was calculated by least squares method.

[0112] Whole Blood Assay for COX-II

[0113] Fresh blood was collected in heparinized tubes by syringe fromvolunteers with consent. The subjects had no apparent inflammatoryconditions and had not taken any medication for at least 7 days prior toblood collection. 500 μl aliquots of human whole blood were incubatedwith either 2 μl dimethyl sulfoxide vehicle or 2 μl of a test compoundat final concentrations for 15 min at 37° C. This was followed byincubation of the blood with 10 μl of 5mg/ml lipopolysaccharide for24hrs at 37° C. for induction of COX-II. Appropriate PBS treatments (noLPS) were used as blanks. At the end of the incubation, the blood wascentrifuged at 6000Xg for 5 min at 4° C. to obtain plasma. A 100 μlaliquot of plasma was mixed with 400 μl methanol for proteinprecipitation. The supernatant was obtained by centrifuging at 6000Xgfor 5 min at 4° C. and was assayed for prostaglandin E₂ (PGE₂) using aradioimmunoassay kit after conversion of PGE₂ to its methyl oximatederivative according to the manufacturer's procedure.

[0114] For a test compound, the results were expressed as percentinhibition of PGE₂ production relative to control incubations containingdimethyl sulfoxide vehicle. The data were analyzed by that a testcompound at the indicated concentrations was changed log value and wasapplied simple linear regression. IC₅₀ value was calculated by leastsquares method.

[0115] (ii) Test Results: Test Compound COX-I COX-II (Example No.) IC50(μM) IC50 (μM) 23 <0.01 >0.1 28 <0.01 >0.1 61 <0.01 >0.1 181 <0.01 >0.1240 <0.01 >0.1 248 <0.01 >0.1 250 <0.01 >0.1 254 <0.01 >0.1 267 <0.01>0.1

[0116] It appeared, from the above-mentioned Test Results, that thecompound (I) or pharmaceutically acceptable salts thereof of the presentinvention have an inhibiting activity against COX, particularly aselective inhibiting activity against COX-I.

[0117] [C] Inhibiting Activity on Aggregation of Platelet

[0118] (i) Methods

[0119] Preparation of platelet-rich plasma

[0120] Blood from healthy human volunteers was collected into plasticvessels containing 3.8% sodium citrate ({fraction (1/10)} volume). Thesubject had no taken any compounds for at least 7days prior to bloodcollection. Platelet-rich plasma was obtained from the supernatantfraction of blood after centrifugation at 1200rpm. for 10 min.Platelet-poor plasma was obtained by centrifugation of the remainingblood at 3000rpm for 10 min.

[0121] Measurement of Platelet Aggregation

[0122] Platelet aggregation was measured according to the turbidimetricmethod with an aggregometer (Hema Tracer) In the cuvette, platelet-richplasma was pre-incubated for 2min at 37° C. after the addition ofcompounds or vehicle. In order to quantify the inhibitory effects ofeach compound, the maximum increase in light transmission was determinedfrom the aggregation curve for 7min after the addition of agonist. Weused collagen as agonist of platelet aggregation in this study. Thefinal concentration of collagen was 0.5μg/mL. The effect of eachcompound was expressed as percentage inhibition agonist-induced plateletaggregation compared with vehicle treatment. Data are presented as themean +S.E.M. for six experiments. The IC₅₀ value was obtained by linearregression, and is expressed as the compound concentration required toproduce 50% inhibition of agonist-induced platelet aggregation incomparison to vehicle treatment.

[0123] It appeared, from the above-mentioned Test Result, that thecompound (I) or pharmaceutically acceptable salts thereof of the presentinvention have an inhibiting activity against platelet aggregation.Therefore, the compound (I) or pharmaceutically acceptable salts thereofare useful for preventing or treating disorders induced by plateletaggregation, such as thrombosis.

[0124] Additionally, it was further confirmed that the compounds (I) ofthe present invention lack undesired side-effects of non-selectiveNSAIDs, such as gastrointestinal disorders, bleeding, renal toxicity,cardiovascular affection, etc.

[0125] As shown above, the object compound (I) or pharmaceuticallyacceptable salts thereof of this invention possesses COX inhibitingactivity and possesses strong anti-inflammatory, antipyretic, analgesic,antithrombotic, anti-cancer activities, and so on.

[0126] The object compound (I) and pharmaceutically acceptable saltthereof, therefore, are useful for treating and/or preventing COXmediated diseases, inflammatory conditions, various pains, collagendiseases, autoimmune diseases, various immunological diseases,thrombosis, cancer and neurodegenerative diseases in human beings oranimals by using administered systemically or topically.

[0127] More particularly, the object compound (I) and pharmaceuticallyacceptable salts thereof are useful for treating and/or preventinginflammation and acute or chronic pain in joint and muscle [e.g.rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, goutyarthritis, juvenile arthritis, scapulohumeral periarthritis, cervicalsyndrome, etc.]; lumbago; inflammatory skin condition [e.g. sunburn,burns, eczema, dermatitis, etc.]; inflammatory eye condition [e.g.conjunctivitis, etc.]; lung disorder in which inflammation is involved[e.g. asthma, bronchitis, pigeon fancier's disease, farmer's lung,etc.]; condition of the gastrointestinal tract associated withinflammation [e.g. aphthous ulcer, Chrohn's disease, atopic gastritis,gastritis varioloid, ulcerative colitis, coeliac disease, regionalileitis, irritable bowel syndrome, etc.]; gingivitis; menorrhalgia;inflammation, pain and tumescence after operation or injury [pain afterodontectomy, etc.] ; pyrexia, pain and other conditions associated withinflammation, particularly those in which lipoxygenase andcyclooxygenase products are a factor, systemic lupus erythematosus,scleroderma, polymyositis, tendinitis, bursitis, periarteritis nodose,rheumatic fever, Sjogren's syndrome, Behcet disease, thyroiditis, type Idiabetes, nephrotic syndrome, aplastic anemia, myasthenia gravis,uveitis contact dermatitis, psoriasis, Kawasaki disease, sarcoidosis,Hodgkin's disease, Alzheimers disease, or the like.

[0128] Additionally, the objectcompound (I) orasaltthereof is expectedto be useful as therapeutical and/or preventive agents forcardiovascular or cerebrovascular diseases, the diseases caused byhyperglycemia and hyperlipemia.

[0129] The object compound (I) and a salt thereof can be used forprophylactic and therapeutic treatment of arterial thrombosis, arterialsclerosis, ischemic heart diseases [e.g. angina pectoris (e.g. stableangina pectoris, unstable angina pectoris including imminent infarction,etc.), myocardial infarction (e.g. acute myocardial infarction, etc.),coronary thrombosis, etc.], ischemic brain diseases [e.g. cerebralinfarction (e.g. acute cerebral thrombosis, etc.), cerebral thrombosis(e.g. cerebral embolism, etc.), transient cerebral ischemia (e.g.transient ischemic attack, etc.), cerebrovascular spasm after cerebralhemorrhage (e.g. cerebrovascular spasm after subarachnoid hemorrhage,etc.), etc.], pulmonary vascular diseases (e.g. pulmonary thrombosis,pulmonary embolism etc.), peripheral circulatory disorder [e.g.arteriosclerosis obliterans, thromboangiitis obliterans (i.e. Buerger'sdisease), Raynaud's disease, complication of diabetes mellitus (e.g.diabetic angiopathy, diabetic neuropathy, etc.), phiebothrombosis (e.g.deep vein thrombosis, etc.), etc.], complication of tumors (e.g.compression thrombosis), abortion [e.g. placental thrombosis, etc.],restenosis and reocclusion [e.g. restenosis and/or reocclusion afterpercutaneous transluminal coronary angioplasty (PTCA), restenosis andreocclusion after the administration of thrombolytic drug (e.g.tissueplasminogen activator (TPA), etc.)], thrombus formation in case ofvascular surgery, valve replacement, extracorporeal circulation [e.g.surgery (e.g. open heart surgery, pump-oxygenator, etc.) hemodialysis,etc.] or transplantation, disseminated intravascular coagulation (DIC),thrombotic thrombocytopenia, essential thrombocytosis, inflammation(e.g. nephritis, etc.), immunediseases, atrophicthrombosis, creepingthrombosis, dilation thrombosis, jumping thrombosis, mural thrombosis,etc..

[0130] The object compound (I) and a salt thereof can be used for theadjuvant therapy with thrombolytic drug (e.g. TPA, etc.) oranticoagulant (e.g. heparin, etc.).

[0131] And, the compound (I) is also useful for inhibition of thrombosisduring extra corporeal circulation such as dialysis.

[0132] Particularly, the following diseases are exemplified: painscaused by or associated with rheumatoid arthritis, osteoarthritis,lumbar rheumatism, rheumatoid spondylitis, gouty arthritis, juvenilearthritis, etc; lumbago; cervico-omo-brachial syndrome; scapulohumeralperiarthritis; pain and tumescence after operation or injury; etc..

[0133] And on the commercial package comprising the pharmaceuticalcomposition mentioned above, the matter, which states above mentionedeffects, may be written.

[0134] For therapeutic purpose, the compound (I) and a pharmaceuticallyacceptable salt thereof of the present invention can be used in a formof pharmaceutical preparation containing said compounds as an activeingredient, in admixture with a pharmaceutically acceptable carrier suchas an organic or inorganic solid or liquid excipient suitable for oral,parenteral or external administration. The pharmaceutical preparationsmay be capsules, tablets, dragees, granules, inhalant, suppositories,solution, lotion, suspension, emulsion, ointment, gel, cream, or thelike. If desired, there may be included in these preparations, auxiliarysubstances, stabilizing agents, wetting or emulsifying agents, buffersand other commonly used additives.

[0135] For therapeutic purpose, the analgesic agent of the presentinvention can be used in a form of pharmaceutical preparation suitablefor oral, parenteral or external administration. The pharmaceuticalpreparations may be capsules, tablets, dragees, granules, inhalant,suppositories, solution, lotion, suspension, emulsion, ointment, gel, orthe like.

[0136] Particularly, the analgesic agent of this invention is useful fortreating or preventing acute or chronic pains associated with acute orchronic inflammations in human beings or animals by using administeredsystemically or topically.

[0137] While the dosage of therapeutically effective amount of thecompound (I) will vary depending upon the age and condition of eachindividual patient, an average single dose of about 0.01 mg, 0.1 mg, 1mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I)may be effective for treating the above-mentioned diseases. In general,amounts between 0.01 mg/body and about 1,000 mg/body may be administeredper day.

[0138] In the above and subsequent description of the presentspecification, the following abbreviations and acronyms mean ones asshown in the following table. Abbreviations and Acronyms Full Name AcOEtor EtOAc ethyl acetate AcOH acetic acid BuOH, t-BuOH, butanol, t-butylalcohol, etc. etc. DME 1,2-dimethoxyethane DMF N,N-dimethylformamideDMSO dimethyl sulfoxide Et3N triethylamine EtOH ethanol IPE diisopropylether MeOH methanol PrOH, i-PrOH or propanol, isopropyl alcohol, etc.IPA, etc. TFA trifluoroacetic acid THF tetrahydrofuran EDCI or WSCD1-ethyl-3-[3′-(dimethylamino)propyl]carbodiimide HOBt or HOBT1-hydroxybenztriazole Pd/C palladium on carbon MCBA or mCPBA or3-Chloroperoxybenzoic acid mcpba deg ° C. = degree centigrade minminute(s) hr or h hour(s) conc. concentrated aq aqueous (ex. aq NaHCO3solution)

[0139] The following Examples and Preparations are given only for thepurpose of illustrating the present invention in more detail.

[0140] Example 1-1

[0141] (1E)-1-[4-(Methoxymethoxy)phenyl]-4-methyl-l-penten-3-one 1MSodium hydroxide aqueous solution (5.4ml) was added to a solution of4-mehoxymethoxybenzaldehyde (4.52g) and 3-methyl-2-butanone (4.69g) inethanol (27ml), and the mixture was stirred at room temperatureovernight.

[0142] The mixture partitionedbetween ethyl acetate andwater. Theorganic layer was washed with water, saturated aqueous sodium chloridesolution, dried over magnesium sulfate, and concentrated in vacuo. Theresidue was purified by silica gel chromatography eluted with 10% ethylacetate/n-hexane to give the title compound (4.03g, 63.2%) as an oil.

[0143] 1HNMR (CDCl₃) : δ 1.18(6H, d, J=6.7Hz), 2.92(1H,m), 3.48(3H,s),5.21(2H,s), 6.71(lH,d,J=16.OHz),7.05(2H,d,J=8.8Hz), 7.51(2H, d,J=8.8Hz), 7.58(1H, d, J=16.OHz). MS (ESI+) : m/z 257 (M+Na).

[0144] Example 1-2

[0145] (1S,2R)- and(lR,2S)-1,2-epoxy-l-[4-(methoxymethoxy)-phenyl]-4-methyl-3-pentanone

[0146] 30%H₂O₂ (1.7ml) and 3M sodium hydroxide aqueous solution (1.7ml)was added to a solution of(1E)-1-[4-(methoxymethoxy)phenyl]-4-methyl-1-penten-3-one obtained byExample 1-1 (2.00g) in ethanol:acetone=3:1 (34ml). The mixture wasstirred at room temperature overnight.

[0147] The mixture was concentrated in vacuo, and partitioned betweenethyl acetate and water. The orgaflic layer was washed with water,saturated aqueous sodium chloride solution, dried over magnesiumsulfate, and concentrated in vacuo to give the target compound (2.03g,95%) as an oil. 1H NMR (DMSO-d6) : δ1.05(6H, d, J=6.9Hz), 2.85(1H, m),3.36(3H, s), 3.93(lH, d, J=1.9Hz), 4.00(1H, d, J=1.9Hz), 5.20(2H, s),7.03(2H, d, J=8.6Hz), 7.30(2H, d, J=8.6Hz). MS (ESI) : m/z 273 (M+Na).

[0148] Example 1-3

[0149] 4-[3-Isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenol

[0150] A mixture of (1S,2R)- and(1R,2S)-1,2-epoxy-1-[4-(methoxymeth-oxy)phenyl]-4-methyl-3-pentanoneobtained by Example 1-2 (2.10g) and 4-methoxyphenylhydrazinehydrochloride (1.76g) in ethanol:acetic acid=20:1 (20ml) was stirred at60° C. for 3hrs.

[0151] The mixture was concentrated in vacuo. To the residue was addedethyl acetate and 1M hydrochloric acid. The whole mixture was treatedwith activated carbon, and was filtered through a celite pad. Thefiltrate was partitioned. The organic layer was washed successively with1M hydrochloric acid, saturated aqueous sodium bicarbonate solution,saturated aqueous sodium chloride solution, dried over magnesiumsulfate, and concentrated invacuo. The residual solid were collected andwashed with ethyl acetate to give the target compound (322.2mg, 12.5%)as a white powder. 1HNMR (CDCl₃): δ1.33 (6H, d, J=7.OHz) , 3.07 (lH, m), 3.80 (3H, s), 5.18(1H, s), 6.26(1H, s), 6.72(2H, d, J=8.8Hz), 6.83(2H,d, J=9. OHz), 7.08(2H, d, J=8.8Hz), 7.20(2H, d, J=9.OHz). MS (ESI+): m/z309 (M+H)

[0152] Example 2

[0153] tert-Butyl2-{4-[3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy}ethylcarbamate

[0154] Diethylazodicarboxylate (259mg) was added to a mixture of4-[3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol obtained byExample 1-3 (305 mg), 2-t-butoxycarbonylaminoethanol (479 mg), andtriphenylphosphine (390 mg) in tetrahydrofuran (3 ml).

[0155] After stirring at room temperature for 7hrs, diethylazodicarboxylate (17mg) and triphenylphosphine (26mg) was ad ded to thereaction mixture.

[0156] After stirring at room temperature for 1hr, the reaction mixturewas concentrated in vacuo. The residue was purified by silica gel columnchromatography eluted with 30% ethyl acetate/n-hexane to give the targetcompound (396mg, 88.5%) as a solid.

[0157] 1HNMR (CDCl₃): δ1.34(6H, d, J=7.0Hz), 1.45(9H, s), 3.07(1H, m),3.48-3.57(2H, m), 3.80(3H, s), 3.97-4.03(2H, m), 4.97(1H, br-s),6.26(1H, s), 6.76-6.87(4H, m), 7.14(2H, d, J=8.9Hz), 7.20(2H, d, J=9.0Hz).

[0158] Example 3

[0159]2-{4-[3-Isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy}ethanaminehydrochloride

[0160] 4M Hydrochloric acid/dioxane (2ml) was added to a solution oftert-butyl2-{4-[3-isopropyl-1-(4-methoxy-phenyl)-1H-pyrazol-5-yl]-phenoxy}ethylcarbamateobtained by Example 2 (382mg) in dichloromethane (3ml) at 0° C.

[0161] After stirring at room temperature for 1hr, the reaction mixturewas concentrated in vacuo. The residue was crystallized from a mixtureof isopropanol and ethyl acetate to give the target compound (311mg,94.7%) as a powder.

[0162] 1H NMR (DMSO-d6) : d 1.27(6H, d, J=6.9Hz), 2.95(1H, m),3.14-3.22(2H, m), 3.76(3H, s), 4.14-4.20(2H, m), 6.41(1H, s), 6.93(4H,d, J=8.9Hz), 7.16(4H, d, J=8.9Hz), 8.22(2H, br-s). MS (ESI+) : m/z 352(M+H).

[0163] Example 4

[0164]N-(2-{4-[3-Isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}-ethyl)methanesulfonamide

[0165] Methanesulfonyl chloride (32.2mg) was added to a solution of2-{4-[3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethanaminehydrochloride obtained by Example 3 (90.9mg) and triethylamine (71.1mg)in dichloromethane (2ml). The mixture was stirred at room temperaturefor 2hrs.

[0166] The mixture was concentrated in vacuo, and the residue waspartitioned between ethyl acetate and a mixture of 1M hydrochloric acidand brine. The aqueous layer was reextracted with ethyl acetate. Theorganic layer was washed with saturated aqueous sodium bicarbonatesolution, and saturated aqueous sodium chloride solution, dried overmagnesium sulfate, and concentrated in vacuo. The residue wascrystallized from a mixture of ethyl acetate and isopropylether to givethe target compound (78.0mg, 77.5%) as a white powder.

[0167] MP : 162-163° C. 1H NMR (DMSO-d6) : δ 1.26(6H, d, J=6.9Hz),2.94(3H, s), 2.94(1H, m), 3.25-3.39(2H, m), 3.76(3H, s), 3.98-4.04(2H,m), 6.40(1H, s), 6.90(2H, d, J=8.8Hz), 6.93(2H, d, J=8.9Hz), 7.13(2H, d,J=8.8Hz), 7.15(2H, d, J=8.9Hz), 7.27(lH, s). IR (KBr) : 3122, 2966,2897, 2871, 1614, 1514cm⁻¹.

[0168] Example 5

[0169]N-(2-{4-[3-Isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)ureaTrimethylsilylisocyanate (41.4mg) was added to a solution of2-{4-[3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethanaminehydrochloride obtained by Example 3 (93.0mg) and triethylamine (72.8mg)in dichloromethane (3ml) and the mixture wasstirred at room temperaturefor 3hrs. Trimethylsilylisocyanate (8.3mg) was added and the mixture wasstirred at room temperature for 1.5hrs. Trimethylsilylisocyanate (13.8mg) and triethylamine (12.1mg) was added and the mixture was stirred atroom temperature for 1.5hrs.

[0170] The mixture was concentrated in vacuo, and the residue waspartitioned between chloroform and a mixture of 1M hydrochloric acid andbrine. The aqueous layer was extracted with chloroform. The combinedorganic layer was washed with saturated aqueous sodium bicarbonatesolution and saturated aqueous sodium chloride solution, dried overmagnesium sulfate, and concentrated in vacuo. The residue was purifiedby preparative thin layer silica gel chromatography developed by 10%methanol/chloroform. The separated silica gel was extracted with 10%methanol/chloroformandthe solventwas evaporated invacuo. The residue wascrystallized from a mixture of ethyl acetate and isopropylether to givethe target compound (85.7mg, 90.6%) as a white powder. MP : 100-104° C.

[0171] 1H NMR (DMSO-d6) : δ1.26(6H, d, J=6.9Hz), 2.94(1H, m),3.27-3.36(2H, m), 3.76(3H, s), 3.89-3.96(2H, m), 5.52(2H, s), 6.14(1H,t, J=5.6Hz), 6.39(1H, s), 6.89(2H, d, J=8.7Hz), 6.93(2H, d, J=8.9Hz),7.12(2H, d, J=8.7Hz), 7.15(2H, d, J=8.9Hz). IR (KBr) : 3371, 3190, 2964,2873, 1738, 1684, 1639, 1614, 1543, 1512 cm⁻¹. MS (ESI+) : m/z 395 (M+H)

[0172] Example 6

[0173] tert-Butyl2-{4-[3-(1-hydroxy-1-methylethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamate

[0174] tert-Butyl2-{4-[3-ethoxycarbonyl-1-(4-methoxy-phenyl)-1-H-pyrazol-5-yl]phenoxy}ethylcarbamate(1.37g) in tetrahydrofuran (10ml) was added dropwise to 0.93M solutionof methyl magnesium bromide in tetrahydrofuran (16ml) at 24-27° C. withcooling in a waterbath.

[0175] After stirring at room temperature for 1hr, the mixture waspoured into a mixture of saturated aqueous ammonium chloride solutionand ice. The mixture was extracted with ethyl acetate. The organic layerwas washed with saturated aqueous sodium chloride solution, dried overmagnesium sulfate, and concentrated in vacuo. The residue was purifiedby silica gel column chromatography eluted with70%ethylacetate/n-hexanetogivethetargetcompound (1.17g, 88%) as anamorphous powder. MS (ESI+) : m/z 468(M+H)

[0176] 1H NMR (CDCl₃) : δ45(9H, s), 1.65(6H, s), 2.78(1H, s),3.48-3.57(2H, m), 3.81(3H, s), 3.97-4.03(2H, m), 4.97(1H, br), 6.36(1H,s), 6.78-6.89(4H, m), 7.13(2H, d, J=8.7Hz), 7.21(2H, d, J=8.9Hz).

[0177] Example 7

[0178] tert-Butyl2-{4-[3-isopropenyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamateMethanesulfonyl chloride (367mg) and triethylamine (649mg) were addedsuccessively to a solution of tert-butyl2-{4-[3-(1-hydroxy-1-methylethyl)-1-(4-methoxy-phenyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamateobtained by Example 6 (1.0g) and N,N-dimethylformamide (91.5mg) indichloromethane (10ml) and the mixture was stirred at room temperaturefor 2hrs. Additional methanesulfonyl chloride and triethylamine wereadded until all starting material was consumed with stirring at the sametemperature.

[0179] The reaction mixture was partitioned between ethyl acetate and 1Mhydrochloric acid, and the organic layer was washed with saturatedaqueous sodium bicarbonate solution and saturated aqueous sodiumchloride solution, dried over magnesium sulfate, and concentrated invacuo. The residue was purified by silica gel column chromatographyeluted with 30%ethylacetate/n-hexane to give the target compound (900mg,93.6%) as an amorphous powder.

[0180] 1H NMR (CDCl₃) : δ1.45(9H, s), 2.21(3H, s), 3.48-3.57(2H, m),3.81(3H, s), 3.97-4.03(2H, m), 4.98(1H, br-s), 5.12(1H, br-s), 5.59(1H,br-s), 6.56(1H, s), 6.77-6.87(4H, m), 7.14(2H, d, J=8.7Hz), 7.22(2H, d,J=8.9Hz). MS (ESI+) : m/z 450 (M+H).

[0181] Example 8

[0182] tert-Butyl2-{4-[3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamate

[0183] A mixture of 10% Pd-C 50% wet (65mg) and tert-butyl2-{4-[3-isopropenyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamateobtained by Example 7 (645mg) in tetrahydrofuran (2ml) and methanol(4ml) was hydrogenated under H₂ latm at room temperature for 3hrs.

[0184] The catalyst was removed by filtration. The filtrate and combinedwashings were concentrated in vacuo. The residue was crystallized from amixture of ethyl acetate and isopropyl ether to give the target compound(370mg, 57.1%) as a white powder.

[0185] 1HNMR (CDCl₃): δ 1.34(6H, d, J=7.0Hz), 1.45(9H, s), 3.07(1H, m),3.48-3.57(2H,m), 3.80(3H,s), 3.97-4.03(2H,m), 4.97(1H, br-s), 6.26(1H,s), 6.76-6.87(4H, m), 7.14(2H, d, J=8.9Hz), 7.20(2H, d, J=9.0Hz). MS(ESI+) : m/z 452 (M+H).

[0186] Example 9

[0187] tert-Butyl2-{4-[3-(1-hydroxy-1-methylethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl-carbamate.

[0188] The title compound (624.4mg, 42.9%) was prepared as an amorphouspowder from tert-butyl2-{4-[3-(1-hydroxy-1-methylethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamatein a similar manner to that of

[0189] Example 6.

[0190] 1H NMR (CDCl₃) : δ1.45(9H, s), 1.65(6H, s), 3.49-3.57(3H, m),3.93(3H, s), 3.98-4.04(2H, m), 4.98(1H, br), 6.39(1H, s), 6.72(lH, d,J=8.8Hz), 6.83(2H, d, J=8.8Hz), 7.15(2H, d, J=8.8Hz), 7.54(1H, dd,J=2.8, 8.8Hz), 8.07(1H, d, J=2.8Hz). MS(ESI+) : 469 (M+H).

[0191] Example 10

[0192] tert-Butyl2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamate

[0193] The title compound (495mg, 85.7%) was prepared as an oil fromtert-butyl2-t4-[3-(1-hydroxy-1-methylethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}-ethylcarbamateobtained by Example 9 in a similar manner to that of Example 7.

[0194] 1H NMR (CDCl₃) : δ 1.45(9H, s), 2.20(3H, s), 3.49-3.57(2H, m),3.92(3H, s), 3.98-4.04(2H,m), 4.99(1H, br-s), 5.15(1H, br-s), 5.60(1H,br-s), 6.58(1H, s), 6.72(lH, d, J=8.8Hz), 6.83(2H, d, J=8.7Hz), 7.15(2H,d, J=8.7Hz), 7.55(1H, dd, J=2.6, 8.8Hz), 8.09(1H, d, J=2.6Hz). MS (ESI+): m/z 451 (M+H).

[0195] Example 11

[0196] tert-Butyl2-{4-[3-isopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamate

[0197] The title compound (220mg, quant.) was prepared as a n amorphouspowder from tert-butyl2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}-ethylcarbamateobtained by Example 10 in a similar manne r to that of Example 8.

[0198] 1HNMR (CDCl₃) : δ1.34(6H, d, J=6.8Hz), 1.45(9H, s), 3.07(1H, m),3.48-3.57(2H,m), 3.92(3H,s),3.98-4.04(2H,m), 4.98(1H, br), 6.28(1H, s),6.71(1H, d, J=8.9Hz), 6.82(2H, d, J=8.9Hz), 7.14(2H, d, J=8.9Hz),7.56(1H, dd, J=2.6, 8.9Hz), 8.05(1H, d, J=2.6Hz). MS (ESI+) : m/z 453(M+H).

[0199] Example 12

[0200]2-{4-[3-Isopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethanaminedihydrochloride

[0201] The title compound (257mg, quant.) was prepared as a n amorphouspowder from tert-butyl2-{4-[3-isopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl-carbamateobtained by Example 11 in a similar manner to that of Example 3.

[0202] 1H NMR (DMSO-d6) : δ1.27(6H, d, J=6.9Hz), 2.96(1H, m),3.15-3.23(2H, m), 3.85(3H, s), 4.15-4.21(2H, m), 6.47(1H, s), 6.86(1H,d, J=8.8Hz), 6.97(2H, d, J=8.8Hz), 7.20(2H, d, J=8.8Hz), 7.62(1H, dd,J=2.7, 8.8Hz), 8.01(1H, d, J=2.7Hz), 8.19(2H, s). MS (ESI+) : m/z 353(M+H).

[0203] Example 13

[0204]N-(2-{4-[3-Isopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea

[0205] The title compound (49.9mg, 51.6%) was prepared as a white powderfrom2-{4-[3-isopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethanamineobtained by Example 12 in a similar manner to that of Example 5. MP :106-107° C.

[0206] 1H NMR (DMSO-d6) : δ1.27(6H, d, J=6.9Hz), 2.96(1H, m), 3.27-3.36(2H, m), 3.85(3H, s), 3.94(2H, t, J=5.5Hz), 5.52(2H, s), 6.15(1H, t,J=5.6Hz), 6.45(1H, s), 6.85(1H, d, J=8.8Hz), 6.93(2H, d, J=8.7Hz),7.16(2H, d, J=8.7Hz), 7.60(1H, dd, J=2.6, 8.8Hz), 8.02(1H, d, J=2.6Hz).IR (KBr) : 3400, 3390, 3379, 3352, 2960, 1657, 1608, 1547, 1512, 1500cm⁻¹. MS (ESI+) : m/z 396 (M+H).

[0207] Example 14-1

[0208]5-[4-(Benzyloxy)phenyl]-1-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-amine

[0209] Sodium (3.19g) wasaddedportionwisetoethanol (160ml) After allsodium was dissolved, 4-methoxyphenylhydrazine hydrochloride (14.5g) wasadded in one portion to the solution. The mixture was stirred at roomtemperature for 10 min. To this mixture was added3-(4-benzyloxyphenyl)acrylonitrile (16.3g) in one portion, and themixture was refluxed for 3days.

[0210] Insoluble matter was filtered off, and the filtrate wasconcentrated in vacuo. Ethyl acetate and water were added to the residueand the mixture was stirred at room temperature for lhr. Precipitateswere collected and washed successively with water, ethyl acetate, andair dried to give the target compound (12.57g, 48.6%) as a powder.

[0211] 1H NMR (DMSO-d6) : δ2.49(1H, dd, J=8.3, 16.1Hz), 3.29(1H, dd,J=10.2, 16.1Hz), 3.60(3H, s), 4.69(1H, dd, J=8.3, 10.2Hz), 5.06(2H, s),5.62(2H, s), 6.65(4H, s), 6.97(2H, d, J=8.6Hz), 7.25(2H, d, J=8.6Hz),7.31-7.48(5H, m). MS : (ESI+) : m/z 374 (M+H).

[0212] Example 14-2

[0213] 5-[4-(Benzyloxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-amineMnO₂ (3.5g) was added to a solution of5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-amineobtained by Example 14-1 (12.54g). in N,N-dimethylformamide (65ml) andthe mixture was stirred at 60° C. for 2hrs. MnO₂ (5.3g) was added andthe mixture was stirred at 60° C. for 1hr.

[0214] The mixture was filtered through a celite pad and the pad waswashed with N,N-dimethylformamide. To the filtrate were added ethylacetate and water, and the mixture was stirred at room temperature for1hr. Precipitates were collected and washed with water and air dried.The obtained powder was suspended in hot isopropylether cooled withstirring, collected and washed with isopropylether to give the targetcompound (11.70g, 93.8%) as a powder.

[0215] 1H NMR (DMSO-d6) δ3.74(3H, s), 4.84(2H, s), 5.08(2H, s), 5.73(lH,s), 6.87(2H, d, J=9.0Hz), 6.96(2H, d, J=9.0Hz), 7.03-7.13(4H, m),7.34-7.47(5H, m). MS (ESI+) : m/z 372 (M+H).

[0216] Example 15

[0217]5-[4-(Benzyloxy)phenyl]-1-(4-methoxyphenyl)-N,N-dimethyl-1H-pyrazol-3-amine37% Aqueous formamide solution (6ml) and sodium cyanoborohydride (1.39g)were added successively to a so lution of5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-amine obtainedby Example 14-2 (2.75g) in methanol 30ml. The reaction mixture wasstirred at room temperature for 3days, occasionally adding 37% aqueousformamide solution and sodium cyanoborohydride appropriate amount toconsume all starting material.

[0218] The reaction mixture was concentrated in vacuo, and the residuewas partitioned between ethyl acetate and water. The organic layer waswashed with saturated aqueous sodium chloride solution, dried overmagnesium sulfate, and concentrated in vacuo. The residue was purifiedby silica gel column chromatography eluted with 20% ethylacetate/chloroform to give the target compound (0.88g, 29.8%) as an oil.

[0219] 1H NMR (DMSO-d6) : δ 2.81(6H, s), 3.75(3H, s), 5.08(2H, s),6.03(1H, s), 6.90(2H, d, J=8.9Hz), 6.97(2H, d, J=8.8Hz), 7.06-7.16(4H,m), 7.32-7.46(5H, m) MS (ESI+) : m/z 400 (M+H).

[0220] Example 16

[0221] 4-[3-(Dimethylamino)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol

[0222] A mixture of 5-[4-(benzyloxy)phenyl]-1-(4-methoxy-phenyl)-N,N-dimethyl-1H-pyrazol-3-amine obtained by Example 15 (0.83g) and 10%Pd-C 50% wet (160mg) in acetic acid (8ml) was hydrogenated under H₂ latmat room temperature for 10hrs.

[0223] The catalyst was removed by filtration. The filtrate and combinedwashings were concentrated in vacuo. The residue was purified by silicagel column chromatography eluted with 20% ethyl acetate/chloroform andwas crystallized from a mixture of isopropylether and ethyl acetate togive the target compound (455mg, 70.8%) as a white powder.

[0224] 1H NMR (DMSO-d6) : δ 2.80(6H, s), 3.74(3H, s), 5.96(1H, s),6.69(2H, d, J=8.5Hz), 6.89(2H, d, J=9.0Hz), 7.01(2H, d, J=8.5Hz),7.09(2H, d, J=9.OHz), 9.64(1H, s). MS (ESI+) : m/z 310 (M+H).

[0225] Example 17

[0226] tert-Butyl2-{4-[3-(dimethylamino)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamate

[0227] The title compound (477.1mg, 99.7%) was prepared as an oil from4-[3-(dimethylamino)-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenolobtained by Example 16 in a similar manner to that of Example 2.

[0228] 1H NMR (CDCl₃) : δ 1.45(9H, s), 2.93(6H, s), 3.48-3.54(2 H, m),3.79(3H, s), 3.97-4.03(2H, m), 4.97(1H, br), 5.85 (1H, s), 6.79(2H, d,J=8.7Hz), 6.81(2H, d, J=9.OHz), 7.1 0-7.27(4H, m)

[0229] Example 18

[0230]5-[4-(2-Aminoethoxy)phenyl]-1-(4-methoxyphenyl)-N,N-dimethyl-1-H-pyrazol-3-aminehydrochloride

[0231] The title compound (454mg, quant.) was prepared as an amorphousfrom tert-butyl2-{4-[3-(dimethylamino)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl-carbamateobtained by Example 17 in a similar manner to that of Example 3.

[0232] 1H NMR (DMSO-d6) : δ 2.83(6H, s), 3.16-3.25(2H, m), 3.7 5(3H, s),4.13-4.18(2H, m), 6.06(1H, s), 6.91(2H, d, J=9.0 Hz), 6.94(2H, d,J=8.8Hz), 7.12(2H, d, J=9.0Hz), 7.17(2 H, d, J=8.8Hz), 8.05(2H, br-s).MS (ESI+) : m/z 353 (M+H).

[0233] Example 19

[0234]N-(2-{4-[3-(Dimethylamino)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea

[0235] The title compound (116mg, 55.7%) was prepared as an amorphousfrom5-[4-(2-aminoethoxy)phenyl]-1-(4-methoxyphenyl)-N,N-dimethyl-1H-pyrazol-3-aminehydrochloride obtained by Example 18 in a similar manner to that ofExample 75 described later.

[0236] 1H NMR (DMSO-d6) : δ 2.81(6H, s), 3.29-3.34(2H, m), 3.7 4(3H, s),3.92(2H, t, J=5.6Hz), 5.53(2H, s), 6.03(1H, s), 6.15(1H, t, J=5.6Hz),6.88-6.92(4H, m), 7.04-7.14(4H, m).

[0237] IR (neat) : 3344, 3330, 3321, 1658, 1651, 1643, 1612, 1579, 1564,1554, 1529, 1514 cm^(−1.) MS (ESI+) : m/z 396 (M+H).

[0238] Example 20-1

[0239]5-[4-(Methoxymethoxy)phenyl]-1-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-amine

[0240] The title compound (4.0g, 57.8%) was prepared as a powder from3-(4-methoxymethoxyphenyl)acrylonitrile in a similar manner to that ofExample 14-1.

[0241] 1H NMR (DMSO-d6) : δ 2.49(1H, dd, J=8.3, 16.1Hz), 3.30(1H, dd,J=10.3, 16.1Hz), 3.36(3H, s), 3.59(3H, s), 4.70(1H, dd, J=8.3, 10.3Hz),5.16(2H, s), 5.62(2H, s), 6.65(4H, s), 6.97(2H, d, J=8.6Hz), 7.25(2H, d,J=8.6Hz). MS (ESI+) : m/z 328 (M+H).

[0242] Example 20-2

[0243]5-[4-(Methoxymethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-amine

[0244] The title compound (4.80g, quant.) was prepared as an oil from5-[4-(methoxymethoxy)phenyl]-1-(4-methoxy-phenyl)-4,5-dihydro-1H-pyrazol-3-amineobtained by Example 20-1 in a similar manner to that of Example 14-2.

[0245] 1H NMR (DMSO-d6) : δ 3.36(3H, s), 3.74(3H, s), 4.85(2H, s),5.18(2H, s), 5.74(1H, s), 6.88(2H, d, J=9.0Hz), 6.96 (2H, d, J=8.8Hz),7.02-7.13(4H, m). MS (ESI+) : m/z 326 (M+H).

[0246] Example 21

[0247]3-Chloro-5-[4-(methoxymethoxy)phenyl]-1-(4-methoxy-phenyl)-1H-pyrazole

[0248] A mixture of5-[4-(methoxymethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-amineobtained by Example 20-2 (3.79g), lithium chloride (2.47g), andcopper(II) chloride (3.13g) in acetonitrile (60ml) was stirred at roomtemperature for 10min. To this mixture was added isoamyl nitrite(2.73g), and the mixture was stirred at room temperature for 1hr.

[0249] The mixture was partitioned between ethyl acetate and saturatedaqueous ammonium chloride solution. The organic layer was washed withsaturated aqueous ammonium chloride solution and saturated aqueoussodium chloride solution, dried over magnesium sulfate, and concentratedin vacuo. The residue was purified by silica gel column chromatographyeluted with 30% ethyl acetate/n-hexane. The solvent was evaporated invacuo. The residue was crystallized from a mixture of isopropyl etherand ethyl acetate to give the target compound (2.38g, 59.3%) as a whitepowder.

[0250] 1H NMR (CDCl₃) : δ 3.48(3H, s), 3.82(3H, s), 5.17(2H, s),6.36(1H, s), 6.85(2H, d, J=9.0Hz), 6.95(2H, d, J=8.9Hz), 7.12(2H, d,J=8.9Hz), 7.20(2H, d, J=9.0Hz). MS (ESI+) : m/z 345(M+H).

[0251] Example 22

[0252] 4-[3-Chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol

[0253] To a solution of3-chloro-5-[4-(methoxymethoxy)-phenyl]-1-(4-methoxyphenyl)-1H-pyrazoleobtained by Example 21 (2.35g) in tetrahydrofuran (10ml) and methanol(10ml) was added 36% hydrochloric acid (0.34ml) . The reaction mixturewas stirred at room temperature for lhr, at 50° C. for 1.5hrs, and at60° C. for 1.5hrs.

[0254] The mixture was partitioned between ethyl acetate and water. Theorganic layer was washed with saturated aqueous sodium chloridesolution, dried over magnesium sulfate, and concentrated in vacuo. Theresidue solid was collected and washed with a mixture of isopropyletherand n-hexane to give the target compound (1.99g, 97.1%) as a whitepowder.

[0255] 1H NMR (DMSO-d6) : δ3.78(3H, s), 6.62(1H, s), 6.71(2H, d,J=8.7Hz), 6.96(2H, d, J=9.0Hz), 7.03(2H, d, J=8.7Hz), 7.19(2H, d,J=9.0Hz), 9.80(1H, s). 200MHz 1H NMR (CDCl₃) : 65 3.82 (3H, s) , 5.24(1H, s) , 6.35 (1H, s), 6.75(2H, d, J=8.6Hz), 6.84(2H, d, J=9.0Hz),7.07(2H, d, J=8.6Hz), 7.18(2H, d, J=9.0Hz). MS (ESI+): m/z 301 (M+H).

[0256] Example 23

[0257]2-{4-[3-Chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxylethanolSodium hydride 60% dispersion in mineral oil (31.lmg) was added to asolution of 4- [3-chloro-1- (4-methoxyphenyl)-1H-pyrazol-5-yl]phenolobtained by Example 22 (180mg) in N,N-dimethylformamide (2ml) undercooling in an ice bath. The reaction mixture was stirred at roomtemperature for 1hr. To the reaction mixture was added a solution of2-bromoethyl tert-butyl(dimethyl)silyl ether (258mg) inN,N-dimethylformamide (2ml).

[0258] After stirring at room temperature overnight, the mixture waspoured into ice water. The mixture was extracted with ethyl acetate. Theorganic layer was washed with water and saturated aqueous sodiumchloride solution, dried over magnesium sulfate, and concentrated invacuo. The residue was dissolved in ethanol (3.6ml). To this solutionwas added 36% aqueous hydrochloric acid (0.3ml) . After stirring at roomtemperature for 3 hrs, the mixture was concentrated in vacuo. Theresidue was partitioned between ethyl acetate and saturated aqueoussodium bicarbonate solution. The organic layer was washed with saturatedaqueous sodium chloride solution, dried over magnesium sulfate, andconcentrated in vacuo. The residue was purified by preparative thinlayer silica gel chromatography developed by 70% ethyl acetate/n-hexane.The separate silica gel was extracted with 10% methanol/chloroform andthe solvent was evaporated in vacuo. The residue was crystallized from amixture of isopropylether and ethyl acetate to give the target compound(136.4mg, 66.1%) as a white powder. MP : 114.7-115.5° C.

[0259] 1HNMR (DMSO-d6) : δ 3.64-3.73(2H,m), 3.77(3H, s), 3.97(2H, t,J=4.9Hz), 4.86(1H, t, J=5.4Hz), 6.68(1H, s), 6.91(2H, d, J=8.9Hz),6.96(2H, d, J=8.9Hz), 7.15(2H, d, J=8.9Hz), 7.20(2H, d, J=8.9Hz).IR(KBr) : 3521, 1610, 1518cm-¹. MS (ESI+) : m/z 345 (M+H).

[0260] Example 24

[0261] tert-Butyl2-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamate

[0262] The title compound (329.5mg, 22.3%) was prepared as an amorphousfrom 4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol obtained byExample 22 in a similar manner to that of Example 73 described later.

[0263] 1H NMR (CDCl₃) : δ 145(9H, s), 3.48-3.57(2H, m), 3.81(3H, s),4.00(2H,t,J=5.1 Hz), 4.96(1H,br), 6.35(1H,s), 6.81(2H, d, J=8.8Hz),6.84(2H, d, J=8.9Hz), 7.12(2H, d, J=8.8Hz), 7.18(2H, d, J=8.9Hz). MS(ESI+) : m/z 444 (M+H).

[0264] Example 25

[0265] tert-Butyl2-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamate

[0266] The title compound (1.31g, 97.8%) was prepared from4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol obtained byExample 22 in a similar manner to that of Example 2. MS (ESI+) : m/z 444(M+H).

[0267] Example 26

[0268]2-14-[3-Chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy}ethanaminehydrochloride

[0269] The title compound (605.2mg, 85.4%) was prepared as a whitepowder from tert-butyl2-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamateobtained by Example 25 in a similar manner to that of Example 3.

[0270] 1H NMR (DMSO-d6) : δ 3.14-3.23(2H, m), 3.78(3H, s),4.14-4.20(2H,m), 6.70(1H,s), 6.96(2H,d,J=8.8Hz), 6.97(2H, d, J=8.9Hz),7.19(2H, d, J=8.8Hz), 7.21(2H, d, J=8.9Hz), 8.19(2H, br-s). MS (ESI+) :m/z 344 (M+H).

[0271] Example 27

[0272]N-(2-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy)ethyl)methanesulfonamide

[0273] The title compound (137.8mg, 82.8%) was prepared as a whitepowder from2-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxylethanaminehydrochloride obtained by Example 26 in a similar manner to that ofExample 4. MP : 117-119° C.

[0274] 1HNMR (DMSO-d6) : δ 2.94 (3H, s) , 3.27-3.34 (2H, m) , 3.76(3H,s), 4.02(2H, t, J=5.5Hz), 6.69(1H, s), 6.90-7.01(4H, m), 7.14-7.25(4H,m), 7.28(1H, t, J=5.7Hz). IR (KBr) : 1612, 1516cm^(−1.) MS (ESI+) : m/z422(M+H).

[0275] Example 28

[0276]N-(2-(4-[3-Chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy}ethyl)urea

[0277] The title compound (174.6mg, 85.8%) was prepared as a whitepowder from2-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethanaminehydrochloride obtain ed by Example 26 in a similar manner to that ofExample 75 described later. MP : 144.8-145.4° C.

[0278] 1HNMR (DMSO-d6) : δ 3.27-3.34(2H,m), 3.77(3H, s), 3.93(2H, t,J=5.5Hz), 5.52(2H, s), 6.15(1H, t, J=5.7Hz), 6.68(1H, s), 6.92(2H, d,J=9.0Hz), 6.97(2H, d, J=9.0Hz), 7.15(2H, d, J=9.0Hz), 7.20(2H, d,J=9.0Hz). IR (ATR) : 3423, 3402, 3203, 3143, 3010, 2976, 2943, 2885,1651, 1610, 1583, 1516 cm⁻¹. MS (ESI+) : m/z 387 (M+H).

[0279] Example 29-1

[0280]5-[4-(Methoxymethoxy)phenyl]-1-(6-methoxy-3-pyridinyl)-4,5-dihydro-1H-pyrazol-3-amine

[0281] The title compound (1.63g, 41.2%) was prepared as a powder from3-(4-methoxymethoxyphenyl)acrylonitrile and2-methoxy-5-pyridinylhydrazine dihydrochloride in a similar manner tothat of Example 14-1.

[0282] H NMR (DMSO-d6) : δ 2.48-2.60(1H, dd, overlapping), 3.23-3.34(1H,dd, overlapping), 3.36(3H, s), 3.68(3H, s), 4.75(1H, dd, J=8.6, 10.0Hz),5.16(2H, s), 5.77(2H, s), 6.56(1H, d, J=8.8Hz), 6.98(2H, d, J=8.6Hz),7.15(1H, dd, J=2.8, 8.8Hz), 7.27(2H, d, J=8.6Hz), 7.49(1H, d, J=2.8Hz)MS (ESI+) : m/z 329 (M+H).

[0283] Example 29-2

[0284]5-[4-(Methoxymethoxy)phenyl]-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-3-amine

[0285] The title compound (1.77g, quant.) was prepared as an oil from5-[4-(methoxymethoxy)phenyl]-1-(6-methoxy-3-pyridinyl)-4,5-dihydro-1H-pyrazol-3-amineobtained by Example 29-1 in a similar manner to that of Example 14-21.

[0286] 1H NMR (DMSO-d6) : δ 3.37(3H, s), 3.83(3H, s), 4.97(2H, s),5.19(2H, s), 5.78(1H, s), 6.81(1H, d, J=8.9Hz), 6.99(2H, d, J=8.8Hz) ,7.15(2H, d, J=8.8Hz) , 7.51(1H, dd, J=2.7, 8.9Hz), 7.92(1H, d, J=2.7Hz)MS (ESI+) : m/z 327 (M+H).

[0287] Example 30

[0288]5-{3-Chloro-5-[4-(methoxymethoxy)phenyl]-1H-pyrazol-1-yl}-2-methoxypyridine

[0289] The title compound (981.7mg, 57.9%) was prepared as a powder from5-[4-(methoxymethoxy)phenyl]l-1(6-methoxy-3-pyridinyl)-1H-pyrazol-3-amineobtained by Example 29-2 in a similar manner to that of Example 21.

[0290] 1H NMR (CDCl₃) : δ 3.48(3H, s), 3.93(3H, s), 5.18(2H, s),6.39(1H, s), 6.74(1H, d, J=8.8Hz), 6.99(2H, d, J=8.8Hz), 7.13(2H, d,J=8.8Hz), 7.55(1H, dd, J=2.7, 8.8Hz), 8.05 (1H, d, J=2.7Hz). MS (ESI+) :m/z 346 (M+H).

[0291] Example 31

[0292] 4-[3-Chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]-phenol

[0293] The title compound (2.15g, 80.5%) was prepared as a white powderfrom5-{3-chloro-5-[4-(methoxymethoxy)-phenyl]-1H-pyrazol-1-yl}-2-methoxypyridineobtained by Example 30 in a similar manner to that of Example 22.

[0294] 1H NMR (DMSO-d6) : δ 3.87(3H, s), 6.68(1H, s), 6.74(2H, d,J=8.6Hz), 6.89(1H, d, J=8.8Hz), 7.07(2H, d, J=8.6Hz), 7.65(1H, dd,J=2.7, 8.8Hz), 8.09(1H, d, J=2.7Hz), 9.86 (1H, br-s). MS (ESI+) : m/z302 (M+H).

[0295] Example 32

[0296]2-{4-[3-Chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy)ethanol

[0297] The title compound (140.9mg, 86%) was prepared as a white powderfrom 4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenolobtained by Example 31 in a similar manner to that of Example 23. MP :136.5-138.2° C.

[0298] 1H NMR (DMSO-d6) : δ 3.65-3.74(2H, m), 3.87(3H, s), 3.9 8(2H, t,J=4.9Hz), 4.87(1H, t, J=5.5Hz), 6.74(1H, s), 6. 86-6.98(3H, m), 7.19(2H,d, J=8.8Hz), 7.67(1H, dd, J=2.8, 8.8Hz), 8.10(1H, d, J=2.8Hz). IR (KBr): 3369, 2960, 1610, 1502cm-1. MS (ESI+) : m/z 346 (M+H).

[0299] Example 33

[0300] tert-Butyl2-{4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1H-prazol-5-yl]phenoxylethylcarbamate

[0301] The title compound (964mg, 93.4%) was prepared as a white solidfrom 4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenolobtained by Example 31 in a similar manner to that of Example 2.

[0302] 1H NMR (DMSO-d6) : δ 1.37(9H, s), 3.22-3.33(2H, m), 3.8 7(3H, s),3.95(2H, t, J=5.7Hz), 6.74(1H, s), 6.86-7.04(4 H, m), 7.19(2H, d,J=8.7Hz), 7.67(1H, dd, J=2.7, 8.8Hz), 8.11(1H, d, J=2.7Hz). MS (ESI+) :m/z 445 (M+H).

[0303] Example 34

[0304]2-{4-[3-Chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}-ethanaminedihydrochloride

[0305] The title compound (842mg, 98.6%) was prepared as an amorphousfrom tert-butyl 2-{4- [3-chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxylethylcarbamate obtainedby Example 33 in a similar manner to that of Example 3.

[0306] 1H NMR (DMSO-d6) : δ 3.15-3.24(2H, m), 3.87(3H, s), 4.1 9(2H, t,J=4.9Hz), 6.76(1H, s), 6.90(1H, d, J=8.8Hz), 6. 99(2H, d, J=8.8Hz),7.23(2H, d, J=8.8Hz), 7.68(1H, d, J=2.7, 8.8Hz), 8.10(1H, d, J=2.7Hz),8.20(2H, br-s). MS (ESI+) : m/z 345 (M+H).

[0307] Example 35

[0308]N-(2-{4-[3-Chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy)ethyl)urea

[0309] The title compound (119.5mg, 62.4%) was prepared as a whitepowder from2-{4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethanaminedihydrochloride obtained by Example 34 in a similar manner to that ofExample 75 described later. MP : 155.6-157.9° C.

[0310] 1H NMR (DMSO-d6) : δ 3.27-3.34(2H, m), 3.87(3H, s), 3.9 4(2H, t,J=5.5Hz), 5.53(2H, s), 6.15(1H, t, J=5.5Hz), 6. 75(1H, s), 6.89(1H, d,J=8.8Hz), 6.95(2H, d, J=8.8Hz), 7. 19(2H, d, J=8.8Hz), 7.66(1H, dd,J=2.7, 8.8Hz), 8.11(1H, d, J=2.7Hz). IR (KBr) : 3425, 3415, 3319, 1657,1610, 1591, 1581, 1574, 1500 cm-⁻¹.

[0311] Example 365-[4-(Benzyloxy)phenyl]-3-isopropoxy-1-(4-methoxy-phenyl)-1H-pyrazole

[0312] A mixture of5-[4-(benzyloxy)phenyl]-3-hydroxy-1-(4-methoxyphenyl)-1H-pyrazol (2.4g),2-iodopropane (5.4 8g), and potassium carbonate (2.67g) inN,N-dimethyl-formamide (10ml) was stirred at 100° C. for 3hrs.

[0313] The reaction mixture was poured into ice water and the mixturewas extracted with ethyl acetate. The organic layer was washed withwater and saturated aqueous sodium chloride solution, dried overmagnesium sulfate, and concentrated in vacuo. The residue was purifiedby silica gel column chromatography eluted with 20% ethylacetate/n-hexane and the solvent was evaporated in vacuo. The residuewas recrystallized from a mixture of ethyl acetate and n-hexane to givethe target compound (2.14g, 80.1%) asawhite powder.

[0314] 1H NMR (DMSO-d6) : δ 1.31(6H, d, J=6.1 Hz), 3.76(3H, s),4.75(1H,m), 5.08(2H, s), 6.00(1H, s), 6.92(2H, d, J=9.0Hz), 6.97(2H, d,J=8.9Hz), 7.10-7.16(4H, m), 7.34-7.43(5H, m) MS (ESI+) : m/z 415 (M+H).

[0315] Example 37

[0316] 4-[3-Isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenol To asolution of ammonium formate (954mg) in water (2ml) were added ethanol(10ml), a solution of5-[4-(benzyl-oxy)phenyl]-3-isopropoxy-1-(4-methoxyphenyl)-1H-pyrazoleobtained by Example 36 (2.09g) in tetrahydrofuran (10ml), and 10%palladium on carbon 50% wet (200mg) successively. The mixture wasrefluxed for 1hr.

[0317] The catalyst was removed by filtration and washed with ethylacetate. The filtrate and combined washings were concentrated in vacuo.Ethyl acetate and water were added to the residue. Precipitates werecollected and washed with water and ethyl acetate to give the first cropof the target compound (419mg) as a white powder. The filtrate waspartitioned, and the organic layer was saturated aqueous sodium chloridesolution, dried over magnesium sulfate, and concentrated in vacuo. Theresidue crystals were collected and washed with isopropylether to givethe second crop of the target compound (1.19g, 72.5%) as a white powder.

[0318] 1H NMR (DMSO-d6) : δ 1.31(6H, d, J=6.2Hz), 3.75(3H, s), 4.75(1H,m), 5.93(1H, s), 6.70(2H, d, J=8.6Hz), 6.91(2H, d, J=9.0Hz), 7.01(2H, d,J=8.6Hz), 7.11(2H, d, J=9.0Hz), 9.70(1H, s). MS (ESI+) : m/z 325(M+H).

[0319] Example 38

[0320]2-{4-[3-Isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethanol

[0321] The title compound (147.3mg, 88.2%) was prepared as an oil from4-[3-isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol obtained byExample 37 in a similar manner to that of Example 23.

[0322] 1H NMR (CDCl₃) : 1.40(6H, d, J=6.2Hz), 2.02(1H, t, J=5. 8Hz),3.79(3H, s), 3.94-4.00(2H, m), 4.04-4.10(2H, m), 4. 87(1H, m), 5.85(1H,s), 6.81(2H, d, J=9.0Hz), 6.82(2H, d, J=8.9Hz), 7.10-7.21(4H, m). IR(neat) : 3400, 3369, 2974, 2933, 1612, 1514cm⁻¹. MS (ESI+) : m/z 369(M+H).

[0323] Example 39

[0324] tert-Butyl2-{4-[3-isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamate

[0325] The title compound (520mg, 72.2%) was prepared as a white powderfrom 4-[3-isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol obtainedby Example 37 in a similar manner to that of Example 2.

[0326] 1H NMR (DMSO-d6) : δ 1.31(6H, d, J=6.2Hz), 1.37(9H, s),3.22-3.31(2H, m), 3.75(3H, s), 3.90-3.97(2H, m), 4.76(1H, m), 5.99(1H,s), 6.86-6.96(4H, m), 7.01(1H, t, J=5.6Hz), 7.09-7.15(4H, m). MS (ESI+): m/z 467 (M+H).

[0327] Example 40

[0328]2-{4-[3-Isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethanaminehydrochloride

[0329] The title compound (557mg, quant.) was prepared as an amorphousfrom tert-butyl2-{4-[3-isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamateobtained by Example 39 in a similar manner to that of Example 3.

[0330] 1H NMR (DMSO-d6) : δ 1.31(6H, d, J=6.1 Hz), 3.12-3.28(2H, m),3.76(3H, s), 4.00-4.18(2H, m), 4.76(1H, m), 6.01(1H, s), 6.92(2H, d,J=9.0Hz), 6.94(2H, d, J=8.7Hz), 7.10-7. 19(4H, m), 8.06(2H, br-s). MS(ESI+) : m/z 368 (M+H).

[0331] Example 41

[0332]N-(2-{4-[3-Isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)methanesulfonamide

[0333] The title compound (125mg, 79.8%) was prepared as a white powderfrom2-{4-[3-isopropoxy-1-(4-methoxy-phenyl)-1H-pyrazol-5-yl]phenoxy}ethanaminehydrochloride obtained by Example 40 in a similar manner to that ofExample 4. MP : 167.9-168.0OC.

[0334] 1H NMR (DMSO-d6) : δ 1.31(6H, d, J=6.1 Hz), 2.94(3H, s),3.27-3.36 (2H, m), 3.75(3H, s), 3.98-4.05(2H, m)), 4.76(1H, m), 6.00(1H, s), 6.88-6.94(4H, m), 7.12(2H, d, J=9.0Hz), 7.14(2 H, d, J=8.9Hz),7.29(1H, t, J=5.8Hz). IR (KBr) : 3132, 2979, 2939, 1612, 1556,1518cm^(−1.) MS (ESI+) : m/z 446 (M+H).

[0335] Example 42

[0336]N-(2-{4-[3-Isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea

[0337] The title compound (76.3mg, 50.1%) was prepared as a white powderfrom2-{4-[3-isopropoxy-1-(4-methoxy-phenyl)-1H-pyrazol-5-yl]phenoxy}ethanaminehydrochlorid e obtained by Example 40 in a similar manner to that ofExample 75 described later. MP : 139-140° C.

[0338] 1H NMR (DMSO-d6) : δ 1.31(6H, d, J=6.1 Hz), 3.27-3.35(2H, m),3.75(3H, s), 3.89-3.96(2H, m), 4.76(1H, m), 5.53(2H, s), 6.00(1H, s),6.15(1H, t, J=5.7Hz), 6.90(2H, d, J=8. 9Hz), 6.92(2H, d, J=9.0Hz),7.08-7.15(4H, m). IR (KBr) : 3388, 3350, 3332, 1658, 1612, 1579, 1562,1554, 1518 cm^(−1.) MS (ESI+) : m/z 411 (M+H).

[0339] Example 43

[0340] 5-[4-(Benzyloxy)phenyl]-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-3-ol

[0341] To a solution of 3-(4-benzyloxyphenyl)propiolic acid (1g) and1-hydroxybenzotriazole hydrate (643mg) in N-methylpyrrolidone (10ml) wasadded WSCD-HCl (912mg) and the mixture was stirred at room temperaturefor 10min. In another flask, diisopropylethylamine (2.31g) was added toa suspension of 5-hydrazino-2-methoxypyridine dihydrochloride (1.26g) inN-methylpyrrolidone (4ml) and stirred at room temperature until all5-hydrazino-2-methoxypyridine dihydrochloride was dissolved. Thusobtained hydrazine solution was added to the reaction flask and themixture was stirred at room temperature for 1.5hrs.

[0342] The mixture was partitioned between ethyl acetate and 0.1Mhydrochloric acid, and the aqueous layer was reextracted withethylacetate. The combinedorganic layers werewashed with saturated aqueoussodium bicarbonate solution and saturated aqueous sodium chloridesolution, dried over magnesium sulfate, and concentratedin vacuo. Theresidue was dissolved in dichloroethane (15ml) and tetrakis(triphenylphosphine) palladium(0) (45.8mg) was added. The mixture wasrefluxed for 1hr and then concentrated in vacuo. The residue wascrystallized from ethyl acetate to give the target compound (739mg,49.9%) as a powder.

[0343] 1H NMR (DMSO-d6) : δ 3.84(3H, s), 5.10(2H, s), 5.87(1H, s),6.83(1H, d, J=8.7Hz), 7.00(2H, d, J=8.7Hz), 7.16(2H, d, J=8.7Hz),7.29-.7.48(5H, m), 7.54(1H, dd, J=2.6, 8.7Hz), 7.97(1H, d, J=2.6Hz),10.13(1H, s). MS (ESI+) : m/z (M+H).

[0344] Example 44

[0345]5-{5-[4-(Benzyloxy)phenyl]-3-isopropoxy-1H-pyrazol-1-yl}-2-methoxypyridine

[0346] The title compound (1.33g, quant.) was prepared as a powder from5-[4-(benzyloxy)phenyl]-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-3-olobtained by Example 43 in a similar manner to that of Example 36.

[0347] 1H NMR (CDCl₃) : δ 1.40(6H, d, J=6.2Hz), 3.92(3H, s), 4. 86(1H,m), 5.05(2H, s), 5.87(1H, s), 6.69(1H, d, J=8.8H z), 6.91(2H, d,J=8.8Hz), 7.15(2H, d, J=8.8Hz), 7.35-7.4 3(5H, m), 7.51(1H, dd, J=2.7,8.8Hz), 8.04(1H, d, J=2.7H z). MS (ESI+) : m/z 416 (M+H).

[0348] Example 45

[0349] 4-[3-Isopropoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenol

[0350] The title compound (442.5mg, 54.9%) was prepared as a powder from5-{5-[4-(benzyloxy)phenyl]-3-isopropoxy-1H-pyrazol-1-yl}-2-methoxypyridineobtained by Example 44 in a similar manner to that of Example 37.

[0351] 1H NMR (CDCl₃) : δ 1.40(6H, d, J=6.2Hz), 3.91(3H, s), 4. 84(1H,m), 5.80(1H, s), 5.87(1H, s), 6.71(1H, d, J=8.8H z), 6.75(2H, d,J=8.6Hz), 7.08(2H, d, J=8.6Hz), 7.55(1H, dd, J=2.7, 8.8Hz), 8.00(1H, d,J=2.7Hz). MS (ESI+) : m/z 326 (M+H).

[0352] Example 46

[0353]2-{4-[3-Isopropoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy)ethanol

[0354] The title compound (94.6mg, 52.2%) was prepared as a white powderfrom 4-[3-isopropoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenolobtained by Example 45 in a similar manner to that of Example 23. MP74-75° C.

[0355] 1H NMR (CDCl₃) : δ 1.40(6H, d, J=6.1 Hz), 1.99(1H, t, J=6. 1Hz),3.91(3H, s), 3.94-4.00(2H, m), 4.05-4.11(2H, m), 4. 86(1H, m), 5.88(1H,s), 6.69(1H, d, J=8.7Hz), 6.85(2H, d, J=8.7Hz), 7.15(2H, d, J=8.7Hz),7.51(1H, dd, J=2.7, 8.7 Hz), 8.03(1H, d, J=2.7Hz). IR (KBr) : 3350,1612, 1512, 1500cm⁻¹. MS (ESI+) : m/z 370 (M+H).

[0356] Example 47

[0357] tert-Butyl2-{4-[3-isopropoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamate

[0358] The title compound (515.3mg, 87.6%) was prepared as a powder from4-[3-isopropoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenolobtained by Example 45 in a similar manner to that of Example 2.

[0359] 1H NMR (DMSO-d6) : δ 1.32(6H, d, J=6.2Hz), 1.37(9H, s),3.22-3.34(2H, m), 3.84(3H, s), 3.92(2H, t, J=5.7Hz), 4.7 7(1H, m),6.06(1H, s), 6.84(1H, d, J=8.8Hz), 6.91(2H, d, J=8.8Hz), 7.01(1H, t,J=5.5Hz), 7.16(2H, d, J=8.8Hz), 7. 58(1H, dd, J=2.7, 8.8Hz), 7.99(1H, d,J=2.7Hz).

[0360] Example 48

[0361]2-{4-[3-Isopropoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazo-1-5-yl]phenoxy}ethanaminedihydrochloride

[0362] The title compound (531mg, quant.) was prepared as an amorphousfrom tert-butyl2-{4-[3-isopropoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl-carbamateobtained by Example 47 in a similar manner to that of Example 3.

[0363] 1H NMR (DMSO-d6) : δ 1.32(6H, d, J=6.1 Hz), 3.15-3.24(2H, m),3.84(3H, s), 4.19(2H, t, J=4.9Hz), 4.77(1H, m), 6.0 7(1H, s), 6.85(1H,d, J=8.8Hz), 6.97(2H, d, J=8.8Hz), 7. 21(2H, d, J=8.8Hz), 7.60(1H, dd,J=2.7, 8.8Hz), 7.99(1H, d, J=2.7Hz), 8.22(2H, br-s). MS (ESI+) : m/z 369(M+H).

[0364] Example 49

[0365]N-(2-{4-[3-Isopropoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxylethyl)urea

[0366] The title compound (81.4mg, 60.2%) was prepared as a white powderfrom2-{4-[3-isopropoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethanaminedihydrochloride obtained by Example 48 in a similar manner to that ofExample 75 described later. MP : 120° C.

[0367] 1H NMR (DMSO-d6) : δ 1.32(6H, d, J=6.2Hz), 3.27-3.36(2H, m),3.84(3H, s), 3.94(2H, t, J=5.5Hz), 4.77(1H, m), 5.5 2(2H, s), 6.06(1H,s), 6.15(1H, t, J=5.6Hz), 6.84(1H, d, J=8.8Hz), 6.93(2H, d, J=8.8Hz),7.17(2H, d, J=8.8Hz), 7. 58(1H, dd, J=2.7, 8.8Hz), 7.99(1H, d, J=2.7Hz).IR (KBr) : 3400, 3330, 1658, 1612, 1514, 1500cm-1. MS (ESI+) : m/z 412(M+H).

Example 50

[0368]N-(2-{4-[3-Isopropoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxylethyl)methanesulfonamide

[0369] The title compound (94.4mg, 58.4%) was prepared from2-{4-[3-isopropoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethanaminedihydrochloride obtained by Example 48 in a similar manner to that ofExample 4. MP : 121.0-121.6° C.

[0370] 1H NMR (DMSO-d6) : δ 1.32(6H, d, J=6.1 Hz), 2.94(3H, s),3.29-3.34(2H, m), 3.84(3H, s), 4.00-4.06(2H, m), 4.77(1H, m), 6.06(1H,s), 6.85(1H, d, J=8.7Hz), 6.94(2H, d, J=8. 8Hz), 7.18(2H, d, J=8.8Hz),7.28(1H, br-s), 7.58(1H, dd, J=2.7, 8.7Hz), 7.99(1H, d, J=2.7Hz). IR(KBr) : 3242, 1612, 1514, 1502cm-¹. MS (ESI+) m/z 447 (M+H).

[0371] Example 51

[0372]2-{4-[1-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethylmethanesulfonate

[0373] To a solution of2-{4-[1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethanol(2.72 g) and triethylamine (1.55ml) in dichloromethane (30ml) was addeddropwise methanesulfonyl chloride (0.86ml) under ice-cooling. Thereaction mixture was allowed to warm to room temperature and stirred for1hr.

[0374] The reaction mixture was quenched with water. The organic layerwas separated and washed with 1N hydrochloric acid and water, dried oversodium sulfate, filtered and evaporated under reduced pressureto givethetarget compound (3.25g, 98.5%).

[0375] 1 HNMR (CDCl₃) : δ 2.929( 3H, s), 3.072(2H, t, J=6.7Hz),4.427(2H, t, J=6.7Hz), 6.739(1H, ), 7.175(2H, d, J=8.4H z), 7.234(2H, d,J=8.4Hz), 7.253(2H, d, J=8.9Hz), 7.344 (2H, d, J=8.8Hz). MS (ESI+): m/z467 (M+Na).

[0376] Example 52

[0377]2-(2-{4-[1-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethyl)-1H-isoindole-1,3(2H)-dione

[0378] A mixture of 2-{4-[1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethyl methanesulfonate obtained by Example51 (3.2g) and Potassium phthalimide (1.6g) was stirred at 80° C. for5hrs.

[0379] After cooling, the mixture was diluted with water and ethylacetate. The aqueous layer was separated and extracted with ethylacetate (twice). The combined organic layer was washed with water(twice) and brine, dried over magnesium sulfate, filtered and evaporatedunder reduced pressure to give the target compound (1.55g, 43.5%) as apowder.

[0380] 1H NMR (CDCl₃) : δ 1.59(3H, s ), 3.02(2H, t, J=7.3Hz), 3. 94(2H,t, J=7.3Hz), 6.71(1H, s), 7.11(2H, d, J=8.2Hz), 7. 21(2H, d, J=7.6Hz),7.24(2H, d, J=8.4Hz), 7.32(2H, d, J=8.9Hz), 7.70-7.86(4H, m). MS (ESI+): m/z 518 (M+Na).

[0381] Example 53

[0382]2-{4-[1-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethanamine

[0383] A mixture of2-(2-{4-[1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethyl)-1H-isoindole-1,3(2H)-dioneobtained by Example 52 (1.5g) and hydrazine (2.93ml) in acetonitrile(30ml) was stirred at 60° C. for 5hrs.

[0384] After cooling, the mixture was filtered and washed withacetonitrile. The filtrate was evaporated under reduced pressure to givethe target compound (1.1g, quant.) as an oil.

[0385] 1H NMR (CDCl₃): δ 3.09(2H, dd, J=5.6Hz, 9.3Hz), 3.24(2H, dd,J=5.6Hz, 8.6Hz), 5.47(2H, s), 6.69(1H, s), 7.12(1H, d, J=8.2Hz),7.21(1H, d, J=8.2Hz), 7.22(1H, d, J=8.9Hz), 7.32(1H, d, J=8.9Hz). MS(ESI+) : m/z 366 (M+l).

[0386] Example 54

[0387]N-(2-{4-[1-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethyl)methanesulfonamide

[0388] To a solution of2-{4-[1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethanamineobtained by Example 53 (400mg) and triethylamine (0.46ml) indichloromethane (20ml) was added dropwise methanesulfonyl chloride(0.25ml) at room temperature.

[0389] After stirring for 1hr, the reaction mixture was quenched with 1Nhydrochloric acid. The aqueous layer was separated and extracted twicewith chloroform. The combined organic layer was washed with 1Nhydrochloric acid, sodium hydrogencarbonate solution, water, dried oversodium sulfate, filtered and evaporated under reduced pressure. Theresidue was column chromatographed on silica gel(chloroform/methanol=4:1) to give the target compound (166mg,.34.2%) asan oil.

[0390] 1H NMR (CDCl₃): δ 2.899(3H, s), 2.904(2H, t, J=6.9Hz), 3. 417(2H,dt, J=6.7 ,6.8Hz), 4.272(1H, t, J=6.1 Hz), 6.737 (1H, s), 7.178(2H, d,J=8.4Hz), 7.21(2H, d, J=8.4Hz), 7. 255(2H, d, J=8.8Hz), 7.35(2H, d,J=8.8Hz). IR (Film) : 3346, 1657, 1597, 1552, 1496, 1471, 1236, 1163,1136, 1092, 978, 835, 756 cm⁻¹. MS (ESI−): 442 (M-1).

[0391] Example 55

[0392]N-(2-{4-[1-(4-Chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethyl)urea

[0393] To a solution of2-{4-[l-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethanamineobtained by Example 53 (300mg) and triethylamine (0.57ml) indichloromethane (10ml) was added dropwise trimethylsilyl isocyanate(0.555ml) at room temperature.

[0394] After stirring overnight, the reaction mixture was quenched with1N hydrochloric acid. Aqueous layer was separated and extracted twicewith chloroform. The combined organic layer was washed with 1Nhydrochloric acid, sodiumhydrogencarbonate solution, water, dried oversodium sulfate, filtered and evaporated under reduced pressure. Theresidue was column chromatographed on silica gel(chloroform/methanol=4:1) to give the target compound (205mg, 61.1%) asan amorphous.

[0395] 1H NMR (CDCl₃): δ 2.83(2H, t, J=7Hz), 3.43(2H, dt, J=6.6 Hz,6.8Hz), 4.41(2H, s), 4.61(1H, t, J=5.4Hz), 6.72(1H, s), 7.16(4H, s),7.25(2H, d, J=8.8Hz), 7.34(2H, d, J=8.8 Hz). IR (Film): 3346, 1657,1597, 1552, 1496, 1471, 1448, 1375, 1271, 1236, 1163, 1136, 1092, 978,835, 756 cm⁻¹. MS (ESI+) : m/z 431 (M+Na).

[0396] Example 56

[0397]4-[1-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzonitrile

[0398] A mixture of 4-(4,4,4-trifluoro-3-oxobutanoyl)-benzonitrile(1.0g), 4-methoxyphenylhydrazine hydrochloride (760mg), and sodiumacetate (357mg) in acetic acid (10ml) was stirred at 80° C. for 4hrs.

[0399] After cooling, the reaction mixture was poured into water andethyl acetate. The aqueous layer was extracted twice with ethyl acetate.Combined organic layers were washed with saturated sodiumhydrogencarbonate solution (twice), water and brine, dried over sodiumsulfate, and evaporated under reduced pressure to give crude product.The crude product was column chromatographed on silica gel (50ml,n-hexane:ethyl acetate=5:1-4:1) and triturate with petroleum ether togive the target compound (553mg, 38.8%).

[0400] 1H NMR (CDCl₃) : δ 3.84(3H, s), 6.82(1H, s), 6.9(2H, d, J=9Hz),7.2(2H, d, J=9Hz), 7.33(2H, d, J=8.6Hz), 7.62(2H, d, J=8.6Hz). IR (Film): 2229, 1610, 1512, 1468, 1240, 1161, 1132, 839 cm⁻¹. MS (ESI+) : m/z366 (M+Na).

[0401] Example 57

[0402]4-[1-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzyl-aminehydrochloride

[0403] A mixture of4-[1-(4-methoxyphenyl)-3-(trifluoro-methyl)-1H-pyrazol-5-yl]benzonitrileobtained by Example 56 (430mg), Pd/C (100mg) and 1N hydrochloric acid(1.3ml) in methanol (43ml) was stirred under Hydrogen atmosphere for5hrs.

[0404] The reaction mixture was filtered with paper filter, and filtratewas evaporated. After dissolving in methanol, the solution was filteredwith membrane filter. The filtrate was evaporated to give the targetcompound (450mg, 93.6%) as crystals.

[0405] 1H NMR (CDCl₃) : δ 3.79(3H, s), 4.04(2H, br-s), 6.69(1H, s),6.85(2H, d, J=8.9Hz), 7.13(2H, d, J=8.9Hz), 7.24(2H, d, J=9Hz), 7.42(2H,d, J=9Hz). IR (Film) : 2964, 1512, 1468, 1238, 1161, 1130, 976, 837cm^(−1.) MS (ESI+) : m/z 331 (M-Cl-NH₃).

[0406] Example 58

[0407]N-{4-[1-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzyl}methanesulfonamide

[0408] To a solution of4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzylaminehydrochloride obtained by Example 57 (100mg) and triethylamine (0.073ml)in chloroform (10ml) was added dropwise methanesulfonyl chloride(0.04ml) at room temperature.

[0409] After stirring for 1hr, the reaction mixture was partitionedbetween chloroform and water. The organic layer was washed with water,sodium bicarbonate solution, brine, dried over magnesium sulfate,filtered and evaporated under reduced pressure to give the targetcompound (90mg, 81.2%) as an oil.

[0410] 1H NMR (CDCl₃) : δ 2.93(3H, s), 3.82(3H, s), 4.32(2H, d,J=6.2Hz), 4.71(1H, t, J=6.2Hz), 6.73(1H, s), 6.86(2H, d, J=9Hz),7.21(2H, d, J=9Hz), 7.21(2H, d, J=8.3Hz), 7.31 (2H, d, J=8.3Hz). IR(Film) : 3282, 1514, 1321, 1240, 1151, 974, 837cm⁻¹. MASS (ESI+) : m/z426 (M+l).

[0411] Example 59

[0412]4-[3-(Difluoromethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzonitrile

[0413] The title compound (4.5g, 20.6%) was prepared from4-(4,4-difluoro-3-oxobutanoyl)benzonitrile in a similar manner to thatof Example 56.

[0414] 1H NMR (CDCl₃) : 6 3.84(3H, s), 6.77(1H, t, J=54.9Hz), 6. 8(1H,s), 6.9(2H, d, J=9Hz), 7.19(2H, d, J=9Hz), 7.33(2H, d, J=8.6Hz),7.61(2H, d, J=8.6Hz). MS (ESI+) : m/z 348 (M+Na).

[0415] Example 60

[0416]1-{4-[3-(Difluoromethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenyl}methanaminehydrochloride

[0417] The title compound (510mg, 45.4%) was prepared from4-[3-(difluoromethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzonitrileobtained by Example 59 in a similar manner to that of Example 57.

[0418] 1H NMR (DMSO-d6) : 6 3.35(3H, s), 3.79(2H, s), 7.1(1H, t,J=54.5Hz), 6.95(1H, s), 6.99(2H, d, J=8.8Hz), 7.26(2H, d, J=8.8Hz),7.3(2H, d, J=8.3Hz), 7.49(2H, d, J=8.3Hz). MS (ESI-): m/z 365 (M-HCl).

[0419] Example 61

[0420]N-{4-[3-(Difluoromethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}methanesulfonamide

[0421] The title compound (146mg, 65.5%) was prepared from1-{4-[3-(difluoromethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenyl}methanamine hydrochloride obtained by Example 60 in asimilar manner to that of Example 58.

[0422] 1H NMR (CDCl₃) : 6 2.90(3H, s), 3.82(3H, s), 4.31(2H, d,J=6.2Hz), 4.73(1H, t, J=6.2Hz), 6.72(1H, s), 6.77(1H, t, J=55Hz),6.86(2H, d, J=9Hz), 7.19(2H, d, J=9Hz), 7.22(2 H, d, J=8.4Hz), 7.30(2H,d, J=8.4Hz). IR (film) : 3143, 1518, 1508, 1452, 1325, 1244, 1151, 1074,1022, 972, 843, 793 cm⁻¹. MS (ESI-) : m/z 406 (M-1).

[0423] Example 62

[0424]N-{4-[3-(Difluoromethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}urea

[0425] To a solution of1-{4-[3-(difluoromethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenyl}methanaminehydrochloride obtained by Example 60 (100mg) in dichloromethane (1ml)was added dropwise triethylamine (0.163ml) and trimethylsilyl isocyanate(0.01ml) at room temperature.

[0426] The mixture was stirred at room temperature overnight andquenched by adding saturated sodium hydrogencarbonate solution (0.5ml).The mixture was filtered by Chemelute. The elution was evaporated andpurified by preparative thin layer chromatography (0.5mm, 10%methanol/chloroform) to give solid. The solid was added ethyl acetateand n-hexane, and the precipitate was collected by filtration to givethe target compound(160mg, 62.9%).

[0427] 1HNMR (CDCl₃) : δ 3.82(3H, s), 4.35(2H, d, J=6Hz), 4.46(2H,br-s), 4.99(1H, t, J=6Hz) , 6.69(1H, s), 6.76(1H, t, J=55.1 Hz),6.86(2H, d, J=9Hz), 7.14-7.21(6H, m). MS (ESI+) m/z 395 (M+Na). IR(film) : 1657, 1608, 1593, 1550, 15120, 1510, 1467, 1338, 1252, 1171,1088, 1030, 837, 796 cm⁻¹.

[0428] Example 63

[0429]4-[1-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzonitrile

[0430] The title compound (942mg, 86.8%) was prepared from4-(4,4,4-trifluoro-3-oxobutanoyl)benzonitrile in a similar manner tothat of Example 56.

[0431] 1H NMR (CDCl₃) : δ 2.39(3H, s), 6.82(1H, s), 7.15(2H, d,J=8.9Hz), 7.21(2H, d, J=8.8Hz), 7.33(2H, d, J=8.3Hz), 7. 62(2H, d,J=8.3Hz). MS (ESI+): m/z 328 (M+l).

[0432] Example 64

[0433]1-{4-[1-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}methanaminehydrochloride

[0434] The title compound (414mg, 92.1%) was prepared from4-[1-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzonitrileobtained by Example 63 in a similar manner to that of Example 57.

[0435] 1H NMR (DMSO-d6) : δ 2.35(3H, d, J=4.2Hz), 3.35(2H, s), 7.17(1H,s), 7.17-7.29(4H, m), 7.32(2H, d, J=8.1Hz), 7.5 1(2H, d, J=8.2Hz). MS(ESI+): m/z 332 (M+1).

[0436] Example 65

[0437]N-{4-[1-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzyl}urea

[0438] The title compound (81mg, 31.8%) was prepared from1-{4-[1-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}methanamine hydrochloride obtained by Example 64 in asimilar manner to that of Example 62.

[0439] 1H NMR (CDCl₃) : δ 2.36(3H, s), 4.35(2H, d, J=5.9Hz), 4. 50(2H,br-s), 5.02(1H, t, J=5.5Hz), 6.71(1H, s), 7.16(4H, s), 7.20(4H, d,J=5.7Hz). IR (film) : 3344, 1658, 1600, 1552, 1518, 1236, 1159, 1134cm^(−1.) MS (ESI+) : m/z 397 (M+Na).

[0440] Example 66

[0441]4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile

[0442] The title compound (1.05g, 73.8%) was prepared from4-methyl-1-(4,4,4-trifluoro-3-oxobutanoyl)benzene in a similar manner tothat of Example 69 described later. MP : 125.0-125.5° C.

[0443] 1H NMR (CDCl3) : δ 2.39(3H, s), 6.74( 1H, s), 7.10(2H, d,J=8.1Hz), 7.19(2H, d, J=8.2Hz), 7.45(2H, d, J=8.7Hz), 7.65 (2H, d,J=8.7Hz). MS (ESI+) : m/z 350 (M+Na).

[0444] Example 67

[0445]1-{4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl)methanaminehydrochloride

[0446] The title compound (830mg, 92.3%) was prepared from4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1- yl]benzonitrileobtained by Example 66 in a similar manner to that of Example 70described later.

[0447] 1H NMR (DMSO-d6) : δ 2.30(3H, d, J=2.3Hz), 4.07(2H, s), 7.15(1H,s), 7.15(2H, d, J=9.0Hz), 7.21(2H, d, J=8.9Hz), 7.39(2H, d, J=8.5Hz),7.58(2H, d, J=8.5Hz). MS (ESI+) : m/z 332 (M+1).

[0448] Example 68

[0449]N-{4-[5-(4-Methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzyl}urea

[0450] The title compound (65mg, 31.9%) was prepared from1-{4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}methanamine hydrochlorideobtained by Example 67 in a similar manner tothat of Example 72 described later.

[0451] 1H NMR (CDCl₃) δ 2.34(3H, s), 4.34(2H, d, J=5.8Hz), 4. 56(2H,br-s), 5.23(1H, t, J=5.8Hz), 6.71(1H, s), 7.07(2H, d, J=8.7Hz), 7.13(2H,d, J=8..7Hz), 7.24(4H, s). IR (film) : 3344, 1658, 1604, 1552, 1234,1159, 1134cm⁻¹. MS (ESI+) : 397 (M+Na).

[0452] Example 69

[0453]4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzonitrile

[0454] A mixture of 4-methoxy-1-(4,4,4-trifluoro-3-oxobutanoyl)benzene(1.0g), 4-methoxyphenylhydrazine hydrochloride (758mg) and sodiumacetate (367mg) in acetic acid (5ml) was stirred overnight at roomtemperature.

[0455] After then, the reaction mixture was poured into water and ethylacetate. The aqueous layer was extracted twice with ethyl acetate.Combined organic layers were washed with water, saturatedsodiumhydrogencarbonate (twice) and brine, dried over sodium sulfate,and evaporated under reduced pressure to give crude product. The crudeproduct was column chromatographed on silica gel (50ml, n-hexane:ethylacetate=10:1-5:1) to give the target compound (930mg, 66.7%).

[0456] 1H NMR (CDCl₃) : δ 3.84(3H, s), 6.72(1H, s), 6.9(2H, d, J=8.9Hz),7.14(2H, d, J=8.9Hz), 7.46(2H, d, J=8.7Hz), 7.66(2H, d, J=8.7Hz). MS(ESI+) : m/z 366 (M+Na).

[0457] Example 70

[0458]4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzylaminehydrochloride

[0459] A mixture of 4-[5-(4-methoxyphenyl)-3-(trifluoro-methyl)-1H-pyrazol-1-yl]benzonitrile obtained by Example 69(400mg) and 50% wet pd/C (400mg) in ethanol (10ml) and 1N hydrochloricacid (1.2ml) was stirred under hydrogen atmosphere for 8hrs.

[0460] The mixture was filtered and filtrate was evaporated underreduced pressure. The residue was washed with isopropyl ether to givethe target compound (400mg, 89.4%) as a powder.

[0461] 1H NMR (CDCl₃) : δ 3.36(s, 3H), 3.76(d, J=2.4, 2Hz), 6.9 4(d,J=8.7, 2Hz), 7.12(s, 1H), 7.23(d, J=8.7, 2Hz), 7.39 (d, J=8.4, 2Hz),7.59(d, J=8.4, 2Hz). MS (ESI+) : m/z 348 (M+l).

[0462] Example 71

[0463]N-{4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzyl}methanesulfonamide

[0464] To a solution of4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzylaminehydrochloride obtained by Example 70 (150mg) and triethylamine (0.1ml)in dichloromethane (10ml) was added dropwise methanesulfonyl chloride(0.06ml) under ice cooling.

[0465] After stirring for 1hr, the reaction mixture was quenched andpartitioned between chloroform and water. The aqueous layer wasextracted with chloroform. The combined organic layer was washed withwater, 1N hydrochloric acid, saturated sodium hydrogencarbonate solutionand brine, dried over magnesium sulfate, filtered and evaporated underreduced pressure. The residue was chromatographed by high performancedthin layer chromatography to give the target compound (67mg, 40.3%).

[0466] 1H NMR (CDCl₃) : δ 2.91(3H, s), 3.82(s, 3H), 4.35(2H, d,J=6.1Hz), 4.69(1H, t, J=6.1Hz), 6.69(1H, s), 6.84(2H, d, J=8.6Hz),7.13(2H, d, J=8.6Hz), 7.32(2H, d, J=9Hz), 7.3 7 (2H, d, J=9Hz). IR(film) 3207, 1479, 1456, 1323, 1252, 1234, 1146, 1122, 984, 968, 962,841, 802 cm^(−1.) MS (ESI+) : m/z 448 (M+Na).

[0467] Example 72

[0468]N-{4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzyl}urea

[0469] To a solution of4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzylaminehydrochloride obtained by Example 70 (150mg) in water (8ml) and ethanol(4ml) was added sodium cyanate (100mg) under ice cooling.

[0470] After stirring for 3hrs, the reaction mixture was partitionedbetween chloroform and water. The aqueous layer was extracted withchloroform. The combined organic layer was washed with water and brine,dried over magnesium sulfate, filtered and evaporated under reducedpressure. The residue was chromatographed by high performanced thinlayer chromatography to give the target compound (105mg, 69%).

[0471] 1H NMR (CDCl₃) : δ 3.80(3H, s), 4.35(2H, d, J=5.9Hz), 4. 53(2H,br-s), 5.171(1H, t, J=5.7Hz), 6.68(1H, s), 6.84(2 H, d, J=8.7Hz),7.12(2H, d, J=8.7Hz), 7.25(4H, s). MS (ESI+) : m/z 413 (M+Na).

[0472] Example 73

[0473] tert-Butyl2-{4-[1-(4-methoxyphenyl)-3-(trifluoro-methyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamate

[0474] To solution of4-[1-(4-methoxyphenyl)-3-trifluoro-methyl-1H-pyrazol-5-yl]phenol (500g)in N,N-dimethyl-formamide (1.5L) was added sodium hydride (dispersion inmineral oil, 77.8g) over 25min under ice cooling. The mixture was warmedto room temperature over 10min and then stirred at room temperature for30min. A solution of 2-tert-butoxycabonylaminoethyl bromide (469g)(prepared by reacting di-ter-butyl dicarbonate with 2-bromoethylaminehydrobromide) reaction in N,N-dimethylformamide (300ml) was added to themixture over 10min at 25-28° C., and the whole mixture was stirred at60° C. for 6hrs.

[0475] After allowed to stand overnight, the mixture was poured into amixture of water (4.5L) and toluene (3L). The organic layer wasseparated, and the aqueous layer was extracted with toluene (1.5L). Thecombined organic layers were washed with water (1.5LX3) and brine(1.5L), dried over magnesium sulfate, filtered and evaporated to givethe oil (1.02kg). The oil was purified with silica gel columnchromatography [5L, n-hexane (10L), 50% ethyl acetate/n-hexane (30L)] togive the target compound (680g, 95%) as a pale yellow oil. MP :104.7-105.1° C.

[0476] 1HNMR (CDCl₃) : δ 1.45(3H, s), 3.53(2H, dt, J=4Hz), 3.82 (3H, s),4.01(2H, t, J=4Hz), 6.67(1H, s), 6.83(2H, d, J=8Hz), 6.8 7(2H, d,J=8Hz), 7.13(2H, d, J=8Hz), 7.23(2H, d, J=8Hz).

[0477] Example 74

[0478]2-{4-[1-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy)ethanaminehydrochloride

[0479] To a solution of hydrogen chloride in ethyl acetate (4N, 1.0L)was added powdered tert-Butyl 2-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-phenoxy}ethylcarbamateobtained by Example 73 (500g) at 5° C. over 20min.

[0480] After stirring at the same temperature for 30min and then at roomtemperature for 1hr, the mixture was evaporated to give oil (543.12g) .The oil was dissolved in toluene (1.5L) . And then, n-hexane (200ml) andthe target compound (as seeds for crystallization) were added to thesolution. The mixture was stirred at room temperature overnight. And theprecipitate was filtered, washed with toluene (500ml X 2) andisopropylether (650ml), and dried to give the target compound (420.5g,97%) as a white powder. MP : 166.8-168.0° C.

[0481] 1HNMR (DMSO-d6) : δ 3.185(2H, t, J=5Hz), 3.8(3H, s), 4. 215(2H,t, J=5Hz), 6.96-7.05(4H, m), 7.1(1H, s), 7.22-7. 33(4H, m).

[0482] Example 75

[0483]N-(2-{4-[l-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea

[0484]2-{4-[1-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethanaminehydrochloride obtained by Example 74 (400g) and sodium acetate (159g)was dissolved in a mixture of N,N-dimethylformamide (1.4L) and water(0.52L) at 50° C. A solution of potassium cyanate (157g) in water(520ml) was added dropwise to the solution over 15min at 38-40° C. Thewhole solution was stirred at 50° C. for 2hrs.

[0485] The solution was filtered and washed with N,N-dimethylformamide(0.68L) at the same temperature. The filtrate was cooled to roomtemperature, and then water (0.4L) and the target compound (A04 typecrystal) was added as seeds for crystallization to the filtrate, and themixture was stirred at room temperature for 30min. Then water (2.76L)was added dropwise to the mixture over 30min, and the mixture wasstirred at room temperature for 30min. The precipitate was filtered,washed with water (0.8LX3), and dried under reduced pressure at 45° C.overnight to give the target compound (A04 type crystals, 442.01g) as awhite powder.

[0486] 1HNMR (CDCl₃) : δ 3.555(2H, dt, J=5, 6Hz), 3.81(3H, 3), 3.995(2H,t, J=5Hz), 4.67(2H, s), 5.37(1H, t, J=6Hz), 6.66(IH, br-s), 6.79(2H, d,J=8Hz), 6.845(2H, d, J=6Hz), 7.11(2H, d, J=8Hz), 7.19(2H, d, J=8Hz).

[0487] 1HNMR (DMSO-d6): δ 3.28-3.36 (2H, m) , 3.79 (3H, s) , 3. 945(2H,t, J=5Hz), 5.54(2H, br-s), 6.165(1H, t, J=5Hz), 6.92-7.08(5H, m),7.2(2H, d, J=8Hz), 7.28(2H, d, J=8Hz).

[0488] Example 76

[0489] 2-Hydroxy-N-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzyl}acetamide

[0490] To a solution of4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzylaminehydrochloride obtained by Example 57 (46.5mg) in dichloromethane (1.5ml)was added diisopropylethylamine (135 μL) and acetoxyacetylchloride (41.6μL) at 0° C.

[0491] After stirring at room temperature for 3hrs, the mixture wasquenched with water. The whole mixture was extracted with ethyl acetate.The organic layer was washed with brine, dried over magnesium sulfate,filtered and evaporated to give oil (67mg) . The oil was dissolved inmethanol (1.5ml). Potassiumcarbonate (55mg) was addedto the solution.After stirring at room temperature for 3hrs, the mixture was filteredand evaporated to give oil which was purified with preparative thinlayer chromatography (0.5mmX2, 10% methanol/chloroform) to givecolorless oil (42.5mg) . The oil was crystallized from a mixture ofethyl acetate, diisopropylether, and n-hexane with stirring at roomtemperature. The precipitate was filtered and dried to give the targetcompound (33.9mg, 64.8%) as a white powder.

[0492] 1HNMR (CDCl₃) : δ 2.32(1H, t, J=5.2Hz), 3.83(3H, s), 4.2 0(2H, d,J=5.2Hz), 4.51(2H, d, J=6.1 Hz), 6.72(1H, s), 6. 87(2H, d, J=8.9Hz),7.16-7.24(6H, m). MS (ESI+) : 428.2(M+Na).

[0493] Example 77

[0494]2-Hydroxy-N-(2-14-[1-(4-methoxyphenyl)-3-(trifluoro-methyl)-1H-pyrazol-5-yl]phenyl}ethyl)ethanesulfonamide

[0495] To a solution of2-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethanaminehydrochloride and triethylamine in chloroform was added methanesulfonylchloride at room temperature.

[0496] After stirring for 1 hr, the reaction mixture was poured intowater and chloroform. The aqueous layer was separated and extracted withchloroform. The combined organic layer was washed with water and brine,dried over sodium sulfate, filtered and evaporated under reducedpressure. The residue was column chromatographed on silica gel andcrystallized to give the target compound (27.7mg, 23.5%).

[0497] 1HNMR (CDCl₃) : δ 2.78-2.91(2H, m), 3.16(2H, t, J=5.1Hz),3.32-3.43(2H,m), 3.82(3H, s), 3.96(2H,t,J=5.1 Hz), 4.65(1H, t,J=6.2Hz),6.72(1H, s), 6.87(2H,d,J=9.0Hz), 7.12-7.27(6H, m). MS(LC, ESI+),470.21(MH+), 511.17(MHMeCN).

[0498] Example 78-1

[0499] tert-Butyl 2-(4-acetylphenoxy)ethylcarbamate

[0500] To a solution of 4-hydroxyacetophenone (10g) and2-tert-butoxycarbonylaminoethylbromide (24.7g) in N,N-dimethylformamide(50 ml) was added potassium iodide (12.2g) and potassium carbonate(15.2g).

[0501] After stirring at 50° C. overnight, the mixture was quenched withwater and extracted with ethyl acetate (3 times). The combined organiclayers were washed with 1N sodium hydroxide aqueous solution (2 times)andbrine, dried over magnesium sulfate, and evaporated to give oil. Theoil was purified with silica gel column chromatography [500ml, 20% ethylacetate/n-hexane (1000ml), 30% ethyl acetate/n-hexane (1000ml)] to givethe target compound (19.89g, 96.9%) as a white solid.

[0502] 1HNMR(CDCl₃) : δ 1.46(9H, s), 2.56(3H, s), 3.52-3.60(2H, m),4.09(2H, t, J=5.1 Hz), 6.93(2H, d, J=8.9Hz), 7.93(2H, d, J=8.9Hz). MS(ESI+) : 280.09(MH+).

[0503] Example 78-2

[0504] tert-Butyl2-[4-(4,4,4-trifluoro-3-oxobutanoyl)-phenoxy]ethylcarbamate

[0505] A mixture of tert-butyl 2-(4-acetylphenoxy)ethyl-carbamateobtained by Example 78-1 (15g), trifluoroacetic acid (8.95ml),andsodiumethoxide (8.77g) inethanol (45ml) was stirred at 70° C. for2.5hrs.

[0506] The mixture was poured into a mixture of aqueous hydrogenchloride solution (1N) and ethyl acetate. The whole mixture wasextracted with ethyl acetate (2 times). The organic layer was separated,washed with saturated sodium hydrogencarbonate and brine, dried overmagnesium sulfate, and evaporated to give oil (25g). The oil waspurified with silica gel column chromatography [500ml, 30% ethylacetate/n-hexane (1000ml)] to give oil. The oil was dissolved in ethylacetate (5ml) under heating by water bath. n-Hexane (100ml) was added tothe solution, and the solution was cooled to room temperature over 30minunder stirring. And n-hexane (100ml) was added to the mixture. Theprecipitate was filtered and dried to give the target compound (15.956g,79.2%) as an orange powder.

[0507] 1HNMR (CDCl₃) δ 3.40-3.70(2H, m), 4.00-4.20(2H, m), 5.00(1H,br-s), 6.50(1H, s), 6.98(2H, d, J=8.6Hz), 7.93(2H, d, J=8.6Hz).

[0508] Example 78-3

[0509] tert-Butyl2-{4-[1-(4-methoxyphenyl)-3-(trifluoro-methyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamate

[0510] To a suspension of 4-methoxyaniline (100mg) in a mixture ofacetic acid (2ml) and concentrated hydrogen chloride (0.4ml) was addeddropwise a solution of sodium nitrite (61.6mg) in water (0.1ml) over5min at 3° C., and the mixture was stirred at 3° C. for 1hr. To themixture was added dropwise a solution of tin chloride (641mg) inconcentrated hydrogen chloride (0.3ml) at 0° C. over 10min, and then themixture was stirred at 0° C. for 1hr. Acetic acid (5ml) was addeddropwise to the mixture at between −20 and −10° C. over 2min, and thenthe mixture was quenched with a solution of sodium hydroxide (336mg) inwater (2.24ml) at −10° C. over 2min and warmed to room temperature togive a solution containing 4-methoxyphenylhydrazine hydrochloride.

[0511] A solution of tert-butyl2-[4-(4,4,4-trifluoro-3-oxobutanoyl)-phenoxy]ethylcarbamate obtained byExample 78-2 (305mg) was added to the former solution at −10° C., andthen the mixture was stirred at room temperature for 3hrs. The mixturewas poured into a mixture of saturated sodium hydrogen carbonate aqueoussolution (150ml) and ethyl acetate (100ml), and adjusted pH to basic bysodium hydrogencarbonate powder.

[0512] The organic layer was separated and the aqueous layer wasextracted with ethyl acetate (50mlX2). The combined organic layers werewashed with saturated sodium hydrogen carbonate aqueous solution andbrine, dried over magnesium sulfate, filtered, and evaporated to giveoil (450 mg). The oil was purified with silica gel column chromatography[35 ml, 15% ethyl acetate/n-hexane (800 ml)] to give an oil. (343.2mg,88.5%). The oil was dissolved in isopropylether (2ml), and then n-hexane(6ml) was added to the solution. The whole mixture was stirred at roomtemperature for 1hr. And then the precipitate was filtered, washed withn-hexane (10ml), and dried under reduced pressure for 2hrs to give thetarget compound (280.6 mg, 72.4%) as a white powder.

[0513] 1HNMR (CDCl₃) data was identical to authentic sample. 1HNMR(CDCl₃) : δ 1.45(3H, s), 3.53(2H, dt, J=4.4Hz), 3.82(3H, s), 4.01(2H, t,J=4Hz), 6.67(1H, s), 6.83(2H, d, J=8Hz), 6.87(2H, d, J=8Hz), 7.13(2H, d,J=8Hz), 7.23(2H, d, J=8Hz).

[0514] Example 79-1

[0515] 1-[4-(Benzyloxy)phenyl]hydrazine hydrochloride

[0516] To the suspension of 4-benzyloxyaniline (10g) in concentratedhydrogen chloride (100ml) was added dropwise a solution of sodiumnitrite (3.2g) in water (10ml) over lOmin at between −15 and −10° C.,and then the mixture was stirred at 3° C. for 1hr. To the mixture wasadded dropwise a solution of tin chloride (33.5g) in concentratedhydrogen chloride (80ml) at between −20 and −10° C. over 30min, and thenthe mixture stirred at 0° C. for 1hr.

[0517] After cooling to −20° C., the precipitate was filtered, washedwith water (25ml), ethanol (25ml) and ether (50ml), and dried to givethe target compound (10.637g, 100%) as a pale brown powder.

[0518] 1HNMR(DMSO-d6) : δ 5.05(2H, s), 6.93-7.03(4H, m), 7.46-7.28(4H,m).

[0519] Example 79-2

[0520]2-{4-[1-(4-Benzyloxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxyl}ethanaminehydrochloride

[0521] The title compound (12.9g, 87.5%) was prepared from1-[4-(benzyloxy)phenyl]hydrazine hydrochloride obtained by Example 79-1and tert-butyl2-[4-(4,4,4-trifluoro-3-oxobutanoyl)phenoxy]ethylcarbamate obtained byExample 78-2 in a similar manner to that of Example 78-3.

[0522] 1HNMR (DMSO-d6) : δ 3.10-3.30(2H, m), 4.19(2H, t, J=6.3Hz),5.14(2H, s), 6.98(2H, d, J=8.7Hz), 7.09(1H, s), 7.09(2H, d, J=8.9Hz),7.49-7.22(9H, m).

[0523] Example 80

[0524]N-(2-14-[l-[4-(Benzyloxy)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea

[0525] The title compound (10.57g, 84.3%) was prepared from2-{4-[1-(4-benzyloxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxyl}-ethanaminehydrochloride obtained by Example 79-2 in a similar manner to that ofExample 75.

[0526] 1HNMR (CDCl₃) : δ 3.57(2H, td, J=5.7, 5.0Hz), 4.01(2H, t,J=5.0Hz), 4.57(1H,br-s), 5.06(2H,s), 5.20(1H,t,J=5.7Hz), 6.66(1H, s),6.80(2H, d, J=8.7Hz), 6.93(2H, d, J=9.0Hz), 7.12(2H, d, J=8.7Hz),7.21(2H, d, J=9.0Hz), 7.35-7.42(5H, m).

[0527] Example 81

[0528]N-(2-{4-[1-(4-Hydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-phenoxy}ethyl)urea

[0529] To a solution ofN-(2-{4-[l-[4-(benzyloxy)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethyl)ureaobtained by Example 80 (10.33g) in methanol (100ml) was added palladiumon carbon (10% wet, 2g), and the mixture was stirred vigorously at roomtemperature under hydrogen atmosphere for 3hrs. The whole mixture wasfil tered and evaporated to give oil (8.23g). The oil was purified withsilica gel column chromatography [250ml, 3% methanol/chloroform (500ml),5% methanol/chloroform (500ml), and 10% methanol/chloroform (500ml)] togive the target compound (8.07g, 95.4%) as an oil.

[0530] 1HNMR (DMSO-d6) : δ 3.28-3.33(2H, m), 3.94(2H, t, J=5.5 Hz),5.52(2H, br-s), 6.14(1H, br-t, J=5.7Hz), 6.80(2H, d, J=8.7Hz), 6.93(2H,d, J=8.9Hz), 7.05(1H, s), 7.14(2H, d, J=8.7Hz), 7.19(2H, d, J=8.9Hz). MS(ESI+) : 407.10(MH+).

[0531] Example 82

[0532]4-[5-(4-{2-[(Aminocarbonyl)amino]ethoxy}phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenylacetate

[0533] To a mixture ofN-(2-{4-[1-(4-hydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy)ethyl)ureaobtained by Example 81 (148.5mg) in dichloromethane (1.5 ml) was addedpyridine (163μL) and acetic anhydride (45μL), and the mixture wasstirred at room temperature for 1hr and stirred under reflux for 3hrs.

[0534] After evaporation, the mixture was purified with preparative thinlayer chromatography (1.0mm, 10% methanol/chloroform) to give oil. Theoil was crystallized from a mixture of dichloromethane andisopropylether at room temperature to give the target compound (138.6mg,84.6%) as a white powder.

[0535] 1HNMR (CDCl₃) : δ 2.30(3H, s), 3.59(2H, td, J=5.5, 4.9H z),4.04(2H, t, J=4.9Hz), 4.51(2H, br-s), 5.22(1H, br-t, J=5.5Hz), 6.69(1H,s), 6.84(2H, d, J=8.7Hz), 7.10(2H, d, J=8.8Hz), 7.14(2H, d, J=8.7Hz),7.31(2H, d, J=8.9Hz). MS(LC, ESI+) : 449.24(MH+), (ESI−) 492.5(M-H+HCO₂⁻)

[0536] Example 83-1

[0537] 1-(1,3-Benzodioxol-5-yl)hydrazine hydrochloride

[0538] The title compound (1.811g, quant.) was prepared from3,4-(methylenedioxy)aniline in a similar manner to that of Example 79-1.

[0539] 1HNMR (DMSO-d6) δ 5.94(2H, s), 6.53(1H, dd, J=2.2 8.2 Hz),6.80(1H, s), 6.83(1H, d, J=8.2Hz). MS(LS, ESI+): 153.9(MH+)193.99(MH+CH₃CN).

[0540] Example 83-2

[0541] tert-Butyl2-{4-[1-(1,3-benzodioxol-5-yl)-3-(trifluoro-methyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamate

[0542] The title compound (371.3mg, 56.7%) was prepared from tert-butyl2-[4-(4,4,4-trifluoro-3-oxobutanoyl)-phenoxy]ethylcarbamate obtained byExample 78-2 and 1-(1,3-benzodioxol-5-yl)hydrazine hydrochlorideobtained by Example 83-1 in a similar manner to that of Example 78-3.

[0543] NMR (CDCl₃) MA12.048 δ 1.75(9H, s), 3.45-3.60(2H, m), 4.02(2H, t,J=5.1 Hz), 6.02(2H, s), 6.66-6.88(1H, m), 7.1 6(2H, d, J=8.8Hz). MS(LC,ESI+) : 492.22 (MH+), 533.26 (MHMeCN+).

[0544] Example 84

[0545]2-{4-[1-(1,3-Benzodioxol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxylethanamine

[0546] The title compound (181.2mg, 61.5%) was prepared from tert-butyl2-14-[1-(1,3-benzodioxol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethylcarbamateobtained by Example 83-2 in a similar manner to that of Example 74.

[0547] 1HNMR (CDCl₃) : δ 1.75(9H, s), 3.45-3.60(2H, m), 4.02(2H, t,J=5.1 Hz), 6.02(2H, s), 6.66-6.88(1H, m), 7.16(2H, d, J=8.8Hz) MS (LC,ESI+) : 392.09(MH+), 433.16(MHMeCN+).

[0548] Example 85

[0549]N-(2-{4-[1-(1,3-Benzodioxol-5-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea

[0550] The title compound (181.2mg, 90.1%) was prepared from2-{4-[l-(1,3-benzodioxol-5-yl)-3-(trifluoro-methyl)-1H-pyrazol-5-yl]phenoxylethanamineobtained by Example 84 in a similar manner to that of Example 75.

[0551] 1HNMR (CDCl₃) : δ 3.6(2H, td, J=5.0, 5.0Hz), 4.045(2H, t, J=5Hz),4.5(2H, br-s), 5.095(1H, br-t, J=5Hz), 6.01(2H, s), 6.66(1H, s),6.75-6.86(3H, m), 6.84(2H, d, J=8Hz), 7.16(2H, d, J=8Hz)* MS (LC, ESI+): 435.08(MH+).

[0552] Example 86

[0553] tert-Butyl2-({4-[1-(4-methoxyphenyl)-3-(trifluoro-methyl)-1H-pyrazol-5-yl]benzyl}amino)-2-oxoethyl-carbamate

[0554] A mixture of4-[1-(4-methoxyphenyl)-3-(trifluoro-methyl)-1H-pyrazol-5-yl]benzylaminehydrochloride obtained by Example 57, N-tert-butoxycarbonyl-glycine,WSCD and 1-hydroxybenzotriazole hydrate in triethylamine anddichloromethane was stirred at room temperature.

[0555] After stirring for 15hrs, the reaction mixture was poured ontowater and chloroform. The aqueous layer was separated and extracted withchloroform. The combined organic layer was washed with water and brine,dried over sodium sulfate, filtered and evaporated under reducedpressure. The residue was column chromatographed on silica gel andcrystallized to give the target compound (93.5mg, 88.9%).

[0556] 1HNMR (CDCl₃) : δ 1.43(9H, s), 3.82(3H, s), 3.82-3.85(2H, m),4.475(2H, d, J=6Hz), 6.71(1H, s), 6.87(2H, d, J=8Hz), 7.14-7.26(6H, m).MS (ESI+) : 505(MH+).

[0557] Example 87

[0558]2-Amino-N-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzyl}acetamidehydrochloride

[0559] The title compound (62.3mg, 82.9%) was prepared from tert-butyl2-({4-[1-(4-methoxyphenyl)-3-(trifluoro-methyl)-1H-pyrazol-5-yl]benzyl}amino)-2-oxoethyl-carbamateobtained by Example 86 in a similar manner to that of Example 74.

[0560] 1HNMR (DMSO-d6) : δ 3.61(2H, s), 3.79(3H, s), 4.345(2H, d,J=6Hz), 7.005(2H, d, J=lOHz), 7.15(1H, s), 7.22-7.32 (6H, m), 8.09(2H,br-s), 8.93(1H, br-t, J=6Hz). MS (ESI+) : 405.33 (free, MH+).

[0561] Example 88

[0562]N-{4-[1-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzyl}acetamide

[0563] To a solution of 4- [1- (4-methoxyphenyl) -3-(trifluoro-methyl)-1H-pyrazol-5-yl]benzylamine hydrochloride obtained byExample 57 and triethylamine in dichloromethane was added dropwiseacetyl chloride at 0° C.

[0564] After stirring at room temperature for 1hr, the mixture wasquenched with saturated sodium hydrogen carbonate aqueous solution andextracted with ethyl acetate (3 times). The combined organic layers werewashed with 1N hydrochloric acid, water, and brine, dried over magnesiumsulfate, and evaporated to give oil, which was purified with silica gelcolumn chromatography (eluted with 50% ethyl acetate/n-hexane) to giveoil. The oil was crystallized from a mixture of ethyl acetate andn-hexane at 50° C. to give the target compound (52.2mg, 69.3%) as asolid.

[0565] 1HNMR (CDCl₃) 6 2.04(3H, s), 3.83(3H, s), 4.435(2H, d, J=6Hz),6.71(1H, s), 6.87(2H, d, J=8Hz), 7.15-7.26(6H, m) IR (KBr) :1647cm^(−1.) MS (ESI+) 412.1(M+Na).

[0566] Example 89

[0567]N-(2-{4-[1-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-phenyl)ethyl)-1-methyl-1H-imidazole-4-sulfonamide

[0568] The title compound (72mg, 70.8%) was prepared from2-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethanaminehydrochloride in a similar manner to that of Example 77.

[0569] 1HNMR (CDCl₃) : δ 2.83(2H, t, J=8Hz), 3.26(2H, dt, J=6H z),3.75(3H, s), 3.83(3H, s), 5.005(1H, t, J=6Hz), 6.7(1 H, s), 6.88(2H, d,J=8Hz), 7.13(4H, s), 7.22(2H, d, J=8H z), 7.45-7.47(2H, m). MS (ESI+) :528.1 (MNa+).

[0570] Example 90

[0571]N-((1R)-2-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}-1-methylethyl)urea

[0572] To a solution of(1R)-2-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1-H-pyrazol-5-yl]phenoxy}-l-methyl-ethanaminehydrochloride in dichloromethane was added triethylamine andtrimethylsilyl isocyanate at 0° C.

[0573] After stirring for 5hrs, the mixture was quenched with water andextracted with dichloromethane. The combined organic layers were washedwith brine, dried over magnesium sulfate, and evaporated under reducedpressure to give oil, which was purified with preparative thin layerchromatography (1mm, ethyl acetate) to give oil. The oil wascrystallized from a mixture of isopropyl ether, ethyl acetate, andn-hexane to give the target compound as a white solid (22.8mg, 88.1%).

[0574] 1HNMR (CDCl₃) : 6 1.29(3H, d, J=8Hz), 3.82(3H, s), 3.87-3.94(2H,m), 4.07-4.19(1H, m), 4.51(2H, s), 4.87(1H, d, J=8Hz), 6.67(1H, s),6.8-6.89(4H, m), 7.12(2H, d, J=8Hz), 7.215(2H, d, J=10Hz). MS (ESI+) :435.3 (MH+), 476.3(MH+MeCN).

[0575] Example 91

[0576]N-(2-{4-[1-(6-Methoxy-3-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethyl)methanesulfonamide

[0577] The title compound (130mg, 71.8%) was prepared from2-{4-[1-(6-methoxy-3-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethanaminedihydrochloride in a similar manner to that of Example 77.

[0578] 1HNMR (CDCl₃) : ( 3.03(3H, s), 3.555(2H, dt, J=5, 5Hz), 3.94(3H,s), 4.115(2H, t, J=5Hz), 4.785(1H, br-t, J=5Hz), 6.71(1H, s), 6.76(1H,d, J=8Hz), 6.85(2H, d, J=8Hz), 7. 16(2H, d, J=8Hz), 7.555(2H, dd, J=8,2Hz), 8.085(1H, d, J=2Hz). MS (ESI+) : 479.1 (M+Na)+.

[0579] Example 92

[0580] 4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenol

[0581] A mixture of 4-methoxy-1-(4,4,4-trifluoro-3-oxo-butanoyl)benzene(5.0g) and p-hydroxyphenyl hydrazine hydrochloride (3.59g) in aceticacid (30ml) was stirred at room temperature.

[0582] After stirring for 15hrs, toluene and water was added. Theaqueous layer was separated and extracted twice with toluene. Thecombined organic layer was washed with water (twice) and brine, driedover sodium sulfate, filtered and evaporated under reduced pressure. Theresidue was column chromatographed on silica gel to give the targetcompound (4.88g, 71.9%) as crystals.

[0583] 1H NMR (CDCl₃) : 3.80(3H, s), 6.68(1H, s), 6.72(2H, d, J=8.8Hz),6.83(2H, d, J=8.8Hz), 7.12(2H, d, J=8.8Hz), 7.13(2H, d, J=8.8Hz). MS(ESI+) : m/z 357 (M+Na).

[0584] Example 93

[0585]2-{4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}ethanol

[0586] A suspension of4-[5-(4-methoxyphenyl)-3-(tri-fluoromethyl)-1H-pyrazol-1-yl]phenolobtained by Example 92 (500mg), potassium carbonate (1.24g), potassiumiodide (1.49g), and 2-chloro-1-ethanol (0.60m 1) was stirred at 80° C.for 5hrs.

[0587] After cooling, the reaction mixture was poured into water. Themixture was extracted twice with ethyl acetate, washed with water andbrine, dried over sodium sulfate, filtered and evaporated under reducedpressure. The residue was column chromatographed on silica gel to givethe target compound (545mg, 96.4%).

[0588] 1H NMR (CDCl₃) : δ 2.03(1H, t, J=5.8Hz), 3.81(3H, s), 3.94-4.01(2H, m), 4.09(2H, dd, J=3.5 ,4.6Hz), 4.52(3H, s), 6.68(1H, s),6.84(2H, d, J=8.9Hz), 6.89(2H, d, J=9Hz), 7.13(2H, d, J=8.9Hz), 7.24(2H,d, J=9Hz). MASS (ESI+) : m/z 401 (M+Na).

[0589] Example 94

[0590]4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}acetonitrile

[0591] A suspension of4-[5-(4-methoxyphenyl)-3-(tri-fluoromethyl)-1H-pyrazol-1-yl]phenolobtained by Example 92 (2.0g), potassium carbonate (992mg), potassiumiodide (993mg), and chloroacetonitrile (0.57m 1) was stirred at 80° C.for 4hrs.

[0592] After cooling, the reaction mixture was poured into water. Themixture was extracted twice with ethyl acetate, washed with water andbrine, dried over sodium sulfate, filtered and evaporated under reducedpressure. The residue was column chromatographed on silica gel to givethe target compound (1.75g, 78.3%) as an oil.

[0593] 1H NMR (CDCl₃) : δ 3.81(3H, s), 4.79(2H, s), 6.69(1H, s),6.86(2H, d, J=8.8Hz), 6.96(2H, d, J=9Hz), 7.14(2H, d, J =8.8Hz),7.31(2H, d, J=9Hz). MS (APCI+) : m/z 374 (M+l).

[0594] Example 95

[0595] tert-Butyl2-{4-[5-(4-methoxyphenyl)-3-(trifluoro-methyl)-1H-pyrazol-1-yl]phenoxy}ethylcarbamate

[0596] The title compound (420mg, 21%) was prepared from4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenolobtained by Example 92 in a similar manner to that of Example 73.

[0597] 1H NMR (CDCl₃) : δ 1.46(9H, s), 3.501-3.58(2H, m), 4.02 (2H, t,J=5.1 Hz), 4.99(1H, br-s), 6.67(1H, s), 6.84(2H, d, J=8.9Hz), 6.85(2H,d, J=9Hz), 7.13(2H, d, J=8.9Hz), 7. 23(2H, d, J=9Hz). MS (ESI+) : m/z500 (M+Na).

[0598] Example 96

[0599]2-{4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}ethanaminehydrochloride

[0600] The title compound (0.35g, 96.2%) was prepared from tert-butyl2-{4-[5-(4-methoxyphenyl)-3-(trifluoro-methyl)-1H-pyrazol-1-yl]phenoxy}ethylcarbamateobtained by Example 95 in a similar manner to that of Example 74.

[0601] 1H NMR (CDCl₃+CD₃OD) : 3.2-3.5(4H, m), 3.81(3H, s), 4. 2-4.35(2H,m), 6.70(1H, s), 6.84(2H, d, J=8.6Hz), 6.95(2 H, d, J=8.6Hz), 7.13(2H,d, J=8.6Hz), 7.25(2H, d, J=8.6H z). MS (ESI+) : m/z 378 (M-Cl).

[0602] Example 97

[0603]N-(2-{4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxytethyl)methanesulfonamide

[0604] To a solution of2-{4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1-H-pyrazol-1-yl]phenoxylethanaminehydrochloride obtained by Example 96 (100mg) in dichloromethane (5ml)and triethylamine (0.1ml) was added dropwise methanesulfonyl chloride(38μl) at room temperature.

[0605] After stirring for 2hrs, the reaction mixture was partitionedbetween chloroform and water. The aqueous layer was extracted withchloroform. The combined organic layer was washed with water and brine,dried over magnesium sulfate, filtered and evaporated under reducedpressure. The residue was purified with high performanced thin layerchromatography to give the target compound (35mg, 31.8%) as crystals.

[0606] 1H NMR (CDCl₃) δ 3.03(3H, s), 3.56(2H, dt, J=5 ,5.7Hz), 3.81(3H,s), 4.11(2H, t, J=5Hz), 4.82(1H, t, J=5.7Hz), 6.68(1H, s), 6.85(2H, d,J=7.9Hz), 6.85(2H, d, J=8.7Hz), 7.13(2H, d, J=8.7Hz), 7.24(2H, d,J=7.9Hz). MS (ESI+) : m/z 478 (M+Na).

[0607] Example 98

[0608]N-(2-{4-[5-(4-Methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-phenoxy}ethyl)urea

[0609] To a solution of2-{4-[5-(4-methoxyphenyl)-3-(tri-fluoromethyl)-1H-pyrazol-1-yl]phenoxy}ethanaminehydrochloride obtained by Example 96 (200mg) in water (10ml) and ethanol(5ml) was added sodium cyanate (314m g) at room temperature.

[0610] After stirring for 15hrs, the reaction mixture was partitionedbetween ethyl acetate and water. The aqueous layer was extracted withethyl acetate. The combined organic layer was washed with water, driedover sodium sulfate, filtered and evaporated under reduced pressure. Theresidue was column chromatography by high performanced thin layerchromatography (chloroform:methanol=8:1) to give the target compound(0.148g, 72.8%).

[0611] 1HNMR (CDCl₃) : δ 3.60(2H, dt, J=5.6, 5.0Hz), 3.81(3H, s),4.04(2H, t, J=5.OHz), 4.50(2H, br-s), 5.12(1H, t, J=5.6Hz), 6.68(1H, s),6.84(2H, d, J=8.8Hz), 6.85(2H, d, J=8.9Hz), 7.13(2H, d, J=8.8Hz),7.22(2H, d, J=8.9Hz). MS (ESI+) : m/z 443 (M+Na).

[0612] Example 99

[0613]N-(2-{4-[3-(Difluoromethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenyl}ethyl)-2-hydroxyethanesulfonamide

[0614] To a solution of2-(2-{4-[1-(4-methoxyphenyl)-3-difluoromethyl-1H-pyrazol-5-yl]phenyl}ethyl)-1H-isoindole-1,3(2H)-dionein acetonitrile was added hydrazine monohydrate.

[0615] After stirring at 60° C. overnight, the mixture was filtered. Andthe filtrate was evaporated to give2-{4-[1-(4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-5-yl]phenyl}ethanamineas an orange oil.

[0616] To a solution of the oil and triethylamine in chloroform wasadded 2-hydroxyethanesulfonyl chloride at room temperature.

[0617] After stirring for 1hr, the reaction mixture was poured ontowater and chloroform. The aqueous layer was separated and extracted withchloroform. The combined organic layer was washed with water and brine,dried over sodium sulfate, filtered and evaporated under reducedpressure. The residue was column chromatographed on silica gel andcrystalized to give the target compound (220mg, 76.1%).

[0618] 1H NMR (CDCl₃) : δ 2.875(2H, t, J=7Hz), 2.91-3.19(2H, m),3.395(2H, dt, J=6Hz), 3.83(3H, s), 3.985(2H, t, J=5Hz), 4.44(1H, br-t,J=6Hz), 6.7(1H, s), 6.765(1H, t, J=55Hz), 6.875(2H, d, J=lOHz), 7.12(6H,s). MS (ESI+) : 452.19(MH+).

[0619] Preparation 1

[0620] To a suspension of AlC13 (45.9g) was added dropwise acetylchloride (13.4ml) (About 5° C.), and then I (25.7g) mentioned aboveunder ice-cooling (5-10° C.). After stirring for 8 hours, the reactionmixture was poured onto ice-water. The organic layer was separated andwashed with water (twice) and 1NHCl, sat.NaHCO3 and brine, dried overMgSO4, filtered and evaporated under reduced pressure to give crudeproduct. The product was distilled under reduced pressure to give 105.8g(84%) of the following compound (P0001)

[0621] TLC Check: Ninhydrin/UV b.p. 1>91-117° C./0.7mmHg. E111271-112.6g 2>117° C./0.7mmHg. E111271-2 105.8g

[0622] Preparation 2

[0623] The above compound P0002 was prepared in a similar manner to thatof P0001.

[0624] Mass (API-ES positive) : 243 (M+Na)+200MHz 1H NMR (CDCl3, d) :1.91-2.05(2H, m), 2.06(3H, s), 2.59(3H, s), 2.76(2H, t, J=7.7 Hz),4.09(2H, t, J=6.5 Hz), 7.28(2H, d, J=8.2 Hz), 7.90(2H, d, J=8.2 Hz)

[0625] Preparation 3

[0626] 60% Sodium hydride 427mg was added to a solution of the compoundP0001 (2g) and ethyl trifluoroacetate 2.6ml in DMF 10ml portionwise (inthree portions) under ice bath cooling. The reaction mixture was stirredat same temperature for 45minutes. Then ice bath was replaced to waterbath. The temperature of reaction mixture was raised to 24.5° C., thenslowly fall down to 22° C. over 1hour. The mixture was stirred at r.t.for 1hour, then poured into a mixture of 1M HCl 12ml and ice 40ml. Thewhole mixture was extracted with AcOEt 20ml. The organic layer waswashed with H2O 30ml, saturated aqueous sodium chloride solution, driedover magnesium sulfate, concentrated in vacuo. The residue was purifiedby silica gel column chromatography eluted with toluene. Obtainedcrystals were washed with chilled n-hexane 10ml and petroleum ether 5mlby decantation to give a compound P0003 as white crystals. mp. 87-88° C.Mass (API-ES negative) 301(M-H)+200MHz 1H NMR (DMSO-d6, d) 3.00(2H, t,J=6.7 Hz), 4.27(2H, t, J=6.7 Hz), 6.99(1H, s), 7.48(2H, d, J=8.3 Hz),8.08(2H, d, J=8.3 Hz)

[0627] Preparation 4

[0628] P0004 was prepared in a similar manner to that of P0003 as shownin Preparation 3. Mass (API-ES negative) : 315 (M-H)+NMR JA24.112 200MHz1H NMR (CDC13, d) : 1.92-2.06(2H, m), 2.06(3H, s),2.74-2.82(2H,m),4.10(2H,t,J=6.5Hz).,6.55(1H,s),7.33(2H, d, J=8.3 Hz),7.89(2H, d, J=8.3 Hz)

[0629] Preparation 5

[0630] P0005 was prepared in a similar manner to that of P0003 as shownin Preparation 3. yellow crystals Mass (API-ES positive) : 259(M+Na)+400MHz 1H NMR (CDCl3, d) : 1.41(3H, t, J=7.1 Hz), 4.40(2H, q,J=7.1 Hz), 6.93(2H, d, J=8.9 Hz), 7.02(1H, s), 7.96(2H, d, J=8.9 Hz)

[0631] Preparation 6

[0632] P0006 was obtained according to a similar manner to that ofP0003. (PREPARATION 3)

[0633] Preparation 7

[0634] 60% Sodium hydride 233mg was added to a solution of P0001 1g andethyl pentafluoropropionate 0.93ml in three portions under ice bathcooling. The reaction mixture was stirred at 24-27° C. with cooling in awater bath for several hours, then poured into a mixture of ice and 1MHCl 50ml. The whole mixture was extracted with AcOEt twice. The combinedorganic layer was washed with saturated aqueous sodium chloridesolution, dried over magnesium sulfate, and concentrated in vacuo togive P0007 1.94g as an oil. Mass (API-ES negative) : 309 (M-H)+200MHz 1HNMR (CDC13, d) : 2.90-3.05(2H, m), 3.85-4.00(2H, m), 6.62(1H, s),7.39(2H, d, J=8.3 Hz), 7.92(2H, d, J=8.3 Hz)

[0635] Preparation 8

[0636] 20% solution of sodium ethoxide in EtOH 18ml was added dropwiseto a solution of P0001 (4.00g) and diethyl oxalate 5.95g in DMF12ml at4-6° C. After stirring at same temperature for 1hour, the reactionmixture was poured into a mixture of ice-water 100ml and conc.HCl 5ml,and extracted with AcOEt. The organic layer was washed successively with1M HCl, H2O, and saturated aqueous sodium chloride solution, dried overmagnesium sulfate, treated with activated carbon, then filtered througha SiO2 (20ml) pad. The pad was washed with AcOEt. The filtrate andcombined washings were concentrated in vacuo to give P0008 (6.05g) as anoil.

[0637] Mass (API-ES positive) : 287(M+Na)+, (API-ES negative)263(M-H)+200MHz 1H NMR (CDC13, d) : 1.42(3H, t, J=7.1Hz), 2.96(2H, t,J=6.5 Hz), 3.93(2H, t, J=6.5 Hz), 4.40(2H, q, J=7.1 Hz), 7.06(1H, s),7.38(2H, d, J=8.3 Hz), 7.96(2H, d, J=8.3Hz)

[0638] Preparation 9

[0639] To a solution of 4-Hydroxybenzophenone (160 g), Ethyltrifluoroacetate (182 ml), and ethanol (11 ml) in N,N-dimethylformamide(670 ml) was added portionwise sodium hydride (suspension in mineraloil, 103 g) over 15 minutes at 0 ˜35° C. The mixture was stirring atroom temperature for 2 hours, and then at 35 ˜40° C. for 3 hours. Themixture was poured into a mixture of ice and concentrated hydrogenchloride (320 ml) (aqueous layer total 4L) and diisopropyl ether (2 L) .The aqueous layer was separated and extracted with diisopropyl ether(500 ml x 2). The combined organic layers were washed with water (500 mlx 4) and brine, dried over magnesium sulfate, and evaporated to give 415g of solid. The solid was dissolved in diisopropyl ether (200 ml) at 65°C. The solution was added dropwise hexane (1.5 L) under stirring at roomtemperature. After stirring at room temperature for 1 hour, Thesuspension was filtered and dried under reduced pressure to give solid(first crop, 109.53 g, 40%). The mother liquid evaporated and similarlytreated diisopropyl ether (20 ml) and hexane (250 ml) to give secondcrop (71.11 g, 26%). P0009 (first corp and second corp total, 66.2%).NMR(CDCl3); 5.65(1H, brs), 6.50(1H, s), 6.94(2H, d, J=8.8 Hz), 7.91(2H,d, J=8.8 Hz). MS(ESI+), 255.1(M+Na)+.

[0640] Preparation 10

[0641] This compound was obtained according to a similar manner to thatof P0009 (S0203744) as a powder (56.195 g, 102%). NMR(CDCl3); 6.01(1H,t, J=54 Hz), 6.49(1H, s), 6.92(2H, d, J=8.8 Hz), 7.90(2H, d, J=8.8 Hz).MS(ESI-), 213.3(M-H)+

[0642] Preparation 11

[0643] A mixture of P0009 (100 g), 4-Methoxyphenylhydrazinehydrochloride (82.4g), and sodium acetate (42.6g) in acetic acid (550ml) was stirring at 70° C. for 3 hours. After cooling to roomtemperature, the mixture was poured into water (4 L) and stirred at roomtemperature for 1 hour. The precipitate was filtered, washed with water(250 ml×3) and Hex(500 ml x 2), and dried at room temperature overnightto give powder (157.86 g). The powder was purified by recrystallizationfrom ethyl acetate and hexane to give P0011 as a powder 121.34G (77%).

[0644] NMR(CDC13);3.82(3H, s), 5.08(1H,brs), 6.67(1H,s), 6.77(2H, d,J=8.6 Hz), 6.87(2H, d, J=9.0 Hz), 7.09(2H, d, J=8.6 Hz), 7.23(2H, d,J=9.0 Hz). MS(ESI+); 357.1(M+Na)+.

[0645] Preparation 12

[0646] This compound was obtained according to a similar manner to thatof P0011 as a solid (3.2028 g, 72%). NMR(DMSO-d6); 3.88(3H, s), 6.74(2H,d, J=8.6 Hz), 6.82(1H, s), 6.90(1H, d, J=8.6 Hz), 7.10(2H, d, J=8.6 Hz),7.09(1H, t, J=55 Hz), 7.68(1H, dd, J=8.6, 2.7 Hz), 8.12(1H, d, J=2.7Hz). MS(ESI+); 316.1(M-H)+, 633.3(2M-H).

[0647] Preparation 13

[0648] This compound was obtained according to a similar manner to thatof P0011.

[0649] Preparation 14

[0650] To a solution of 4-methoxyphenylhydrazine hydrochloride (3.43 g)in water (7.7 ml) was added a solution of P0009 in acetic acid (50 ml).The mixture was then allowed to stand at room temperature overnight. Themixture was poured into water (500 ml) and stirred at room temperaturefor 1 hour. The precipitate was filtered, washed with water (100 ml),and dried at room temperature to give P0014 as a brown solid (3.26 g,90%).

[0651] NMR(DMSO-d6); 3.88(3H, s), 6.75(2H, d, J=8.6 Hz), 6.92(1H, d,J=8.5Hz), 7.06-7.15(3H, m), 7.73(1H, dd, J=8.5, 2.8 Hz), 8.16(1H, d,J=2.8 Hz), 9.86(IH, s, OH). MS(ESI−); 334.1(M-H)+, 669.2(2M-l)+.

[0652] Preparation 15

[0653] This compound was obtained according to a similar manner to thatof P0014 as a pale brown powder (13.58 g, 91.7%). NMR(DMSO-d6); 3.94(3H,s), 6.67(1H, s), 6.75(1H, t, J=55 Hz), 6.73-6.80(3H, m), 7.09(2H, d,J=8.6 Hz), 7.57(1H, dd, J=8.6, 2.6 Hz), 8.07(1H, d, J=2.6 Hz). MS(ESI-);316.1(M-H), 633.3(2M-H).

[0654] Preparation 16

[0655] 1M NaOH lml was added to a solution of P0016-1 (reported inW09427973) 1.31g and in EtOH5ml and the mixture was stirred at amibienttemperature overnight. The mixture partitioned between AcOEt and H2O.The organic layer was washed with H2O, saturated aqueous sodium chloridesolution, dried over magnesium sulfate, and concentrated in vacuo. Theresidue was purified by silica gel column chromatography eluted withAcOEt/n-hexane to give P0016 (900mg) as an oil. Mass (ESI+) : 331 (M+H)+200MHz 1H NMR (DMSO-d6, d): −0.05(6H, s), 0.82(9H, s), 0.94 (4H, d,J=6.0 Hz), 2.38-2.52 (1H, m), 2.78 (2H, t, J=6.6 Hz), 3.79(2H, t,J=6.6Hz), 7.01(1H, d, J=16.2 Hz), 7.29(2H, d, J=8.1 Hz), 7.65(2H, d,J=8.1 Hz), 7.65(1H, d, J=16.2 Hz)

[0656] Preparation 17

[0657] P0017 6.4lg was prepared in a similar manner to that of P0016.Mass (API-ES positive) : 255 (M+Na)+200MHz 1H NMR (CDC13, d)0.90-1.01(2H, m), 1.11-1.20(2H, m), 2.22(1H,m), 3.49(3H, s), 5.21(2H,s), 6.78(1H, d, J=16.0 Hz), 7.05(2H, d, J=8.7 Hz), 7.52(2H, d, J=8.7Hz), 7.58(1H, d, J=16.0 Hz)

[0658] Preparation 18

[0659] 30% H2020.64ml and 3MNaOH 0.64ml was added to a 0.25M solution ofP0016 1.03g in EtOH:acetone=3:1. The mixture was stirred at ambienttemperature overnight. The mixture was concentrated in vacuo, andpartitioned between AcOEt and H2O. The organic layer was washed withH2O, saturated aqueous sodium chloride solution, dried overmagnesiumsulfate, and concentrated in vacuo to give P0018 (792mg) as an oil. Mass(ESI+) : 347 (M+H)+200MHz 1H NMR (DMSO-d6, d) −0.05(6H, s), 0.82(9H, s),0.92-1.04(4H, m), 2.24(1H, m), 2.75(2H, t, J=6.7 Hz), 3.76(2H, t, J=6.7Hz), 3.86(1H, d, J=1.9 Hz), 4.19(1H, d, J=1.9 Hz), 7.24(2H, d,.J=8.4Hz), 7.30(2H, d, J=8.4 Hz)

[0660] Preparation 19

[0661] P0019 1. 082g was prepared from P0017 1.0g in a similar manner tothat of P0018.

[0662] Mass (API-ES positive) : 271(M+Na)+200MHz 1HNMR (DMSO-d6, d) :0.90-1.04(4H, m), 2.24(1H, m), 3.37(3H, s), 3.88(1H, d, J=1.9 Hz),4.17(1H, d, J=1.9 Hz), 5.20(2H, s), 7.03(2H, d, J=8.7 Hz), 7.32(2H, d,J=8.7 Hz) 20OMHz 1HNMR (CDC13, d) : 0.90-1.07(2H, m), 1.12-1.26(2H, m),2.18(1H, m), 3.48(3H, s), 3.58(1H, d, J=1.9Hz), 4.05(1H, d, J=1.9 Hz),5.18(2H, s), 7.04(2H, d, J=8.7 Hz), 7.23(2H, d, J=8.7 Hz)

[0663] Preparation 20

[0664] P0005 17.00g was dissolved in warm EtOH 68ml and ACOH 170ml at70° C. To this solution was added P0005, suspended in H2O 20ml, in oneportion. The mixture was stirred at 70° C. for 1.5hours and then pouredinto a mixture of ice 500ml and conc.HCl 10ml. Diisopropyl ether 100mlwas added and the mixture was stirred at ambient temperature for20minutes. The precipitates were collected and washed successively with1M HCl, H2O, and diisopropylether. This was air dried overnight to giveP0020 21.28g was a pale yellow powder.

[0665] Mass (ESI+) : 339 (M+H)+400MHz 1H NMR (CDC13, d) : 1.41(3H, t,J=7.1 Hz), 3.82(3H, s), 4.44(2H, q, J=7.1 Hz), 6.76(2H, d, J=8.7 Hz),6.85(2H, d, J=9.0 Hz), 6.96(1H, s), 7.08(2H, d, J=8.7 Hz), 7.24(2H, d,J=9.0 Hz)

[0666] Preparation 21

[0667] P0021 was prepared from P0005 in a similar manner to that ofP0020. white powder

[0668] Mass (ESI+) : 340 (M+H)+200MHz 1H NMR (DMSO-d6, d) : 1.31(3H, t,J=7.1 Hz), 3.88(3H, s), 4.32(2H, q, J=7.1 Hz), 6.74(2H, d, J=8.6 Hz),6.92(1H, d, J=8.8 Hz), 7.00(1H, s), 7.09(2H, d, J=8.6 Hz), 7.71(1H, dd,J=8.8,2.7 Hz), 8.13(1H, d, J=2.7 Hz), 9.82(1H, s)

[0669] Preparation 22

[0670] A solution of triphenylphosphine 831mg in THF 5ml was addeddropwise to a solution of E0118 521.8mg and carbon tetrabromide 1.15g inTHF 5ml at ambient temperature. The reacion mixture was stirred atambient temperaturer for 1 hour. Carbon tetrabromide 573mg andtriphenylphosphine 415mg were added in one portion and stirred forfurther lhour. Unsoluble matter was filtered off and washed with THF.The filtrate and combined washings were concentrated in vacuo. Theresidue was purified by silica gel column chromatography eluted withAcOEt/n-hexane =5%, then 25% to give P0022 647.2mg as pale yellow wax.mp.60-70° C.

[0671] Mass (API-ES positive) : 425,427 (M+H)+, 447,449(M+Na)+200MHz 1HNMR (CDCl3, d) : 3.12-3.19(2H, m), 3.52-3.60(2H, m), 3.82(3H, s),6.72(1H, s), 6.87(2H, d, J=9.0 Hz), 7.16-7.30(6H, m)

[0672] Preparation 23

[0673] P0023 was prepared in a similar manner to that of P0022.colorless oil

[0674] Mass (API-ES positive) 448,450 (M+Na)+400MHz 1HNMR (DMSO-d6, d)3.14(2H, t, J=7.2 Hz), 3.74(2H, t, J=7.2 Hz), 3.88(3H, s), 6.92(1H, d,J=8.8 Hz), 7.20(1H, s), 7.27(2H, d, J=8.4 Hz), 7.32(2H, d, J=8.4 Hz),7.76(1H, dd, J=2.7,8.8 Hz), 8.19(1H, d, J=2.7 Hz),

[0675] Preparation 24

[0676] To a solution of P0001 (20.0g) and P0024-0 (53.4g) in DMF (200ml)was added portionwise NaH (4.27g) under ice-cooling. The reactionmixture was warmed at room temperature andthe temperaturewas kept under40° C. After stirring for 5 hours, the reaction mixture was poured ontoice-cooled di1HCl and extracted twise with ethylacetate. The combinedorganic layer was washed with water (twice) To and brine, dried overMgSO4, filtered and evaporated under reduced pressure. The residue wascolumn chromatographed on silica gel (500ml, Hex:EtOAc) to give 12.12gof P0024 as crystal. mp: 52.6-53.6° C.

[0677] Example 100

[0678] To a solution of 4-hydroxybenzophenone (4.16g) and chloromethylmethyl ether (2.46g) in N,N-dimethylacetoamide (15ml) was addedportionwise sodium hydride (suspension in mineral oil (60%), 1.22g) over15 minutes at 0° C. The mixture was stirred for 30 minutes at ambienttemperature. To the reaction mixture was added 2-propanole (0.5ml) ,carbon disulfide (2.56g) and portionwise sodium hydride (suspension inmineral oil (60%), 2.50g) over 15 minutes at 25° C. The mixture wasstirred at ambient temperature for 1.5 hours,diluted with toluene (20ml)and poured into a mixture of ice and concentrated hydrogen chloride (8ml) (aqueous layer total 68ml). The resultant mixture was extracted withethyl acetate, washed with brine,dried over magnesium sulfate, andevaporated. To the mixture of the resultant residue and sodium hydrogencarbonate (13g) in ethyl acetate (30ml) and water (20ml) was addedportionwise the solution of iodine (3.88g) and sodium iodide (8.0g) inwater at 0° C. To the mixture was added portionwise4-Methoxyphenylhydrazine hydrochloride (3.80g) at 0° C. under nitrogen.The mixture was stirred at ambient temperature for 3 hours and theorganic layer was seperated, washed with water and brine, dried overmagnesium sulfate, and evaporated. To the solution of the residue inethyl acetate (30ml) was added methyl iodide (4.0ml) and triethylamine(10ml) at 0° C. The mixture was stirred for 30 minutes at ambienttemperature, washed with water and aqueous potassium carbonate, driedover magnesium sulfate, and evaporated. The residue was columnchromatographed on silica gel (80g) ,eluting with a mixture of ethylacetate andtoluene (1:20) togive7.56gof5-[4-(methoxymethoxy)-phenyl]-1-(4-methoxyphenyl)-3-(methylthio)-1H-pyrazole.

[0679] To the solution of methyl sulfide (7.56g) in dichloromethane (30ml) was added a solution of m-chloroperbenzoic acid (80%,4.4g) indichloromethane (15ml) at 0° C., and the mixture was stirred at 0° C.for 1 hour. The mixture was washed with aqueous potassium carbonate,dried over magnesium sulfate, and evaporated. The residue was columnchromatographed on silica gel (80g) ,eluting with ethyl acetate to give5.43g of5-[4-(methoxymethoxy)phenyl]-1-(4-methoxyphenyl)-3-(methylsulfinyl)-1H-pyrazole(EO100). mp.136.9-137.3° C.

[0680] Mass;373(M+l) IR(KBr);1054cm−1

[0681] NMR(CDCl3,δ) ; 3.00(H, s), 3.48 (H, s), 3.83(H, s), 5.17 (H, s),6.88(H, d, J=9.0 Hz), 6.92(H, s), 6.97 (H, d, J=8.8 Hz), 7.14(H, d,J=8.8 Hz), 7.22(H, d, J=9.0 Hz),

[0682] Example 101

[0683] To the solution of5-[4-(methoxymethoxy)phenyl]-1-(4-methoxyphenyl)-3-(methylsulfinyl)-1H-pyrazole(7.56g) in dichloromethane (20ml) wasadded m-chloroperbenzoic acid(60%,3.76g) at 0° C., and the mixture was stirred at 0° C. for 3 hour.The mixture was washed with aqueous sodium hydrogen carbonate , driedover magnesium sulfate, and evaporated. The residue was purified byrecrystallization with toluene to give 5.07g of5-[4-(methoxymethoxy)phenyl]-1-(4-methoxyphenyl)-3-(methylsulfonyl)-1H-pyrazole(E0101).mp.128.0-128.1° C.

[0684] Mass;389(M+1) IR(KBr);1300cm−1

[0685] NMR(CDC13,δ) ; 3.29(3H, s), 3.48(3H, s), 3.83(3H, s), 5.17(2H,s), 6.88(2H, d, J=9.0 Hz), 6.93(1H, s), 6.98(2H, d, J=8.8 Hz), 7.13(2H,d, J=8.8 Hz), 7.24(2H, d, J=9.0 Hz),

[0686] Preparation 25

[0687] To the solution of5-[4-(methoxymethoxy)phenyl]-1-(4-methoxyphenyl)-3-(methylsulfonyl)-1H-pyrazole(0.93g) in a mixture of tetrahydrofuran (10ml) and isopropyl alcohol(5ml) was added hydrogen chloride aqueous solution (20%,8ml) at ambienttemperature. The solution was stirred for 3 hours, extracted with ethylacetate, washed with brine, dried over magnesium sulfate,and evaporatedto give 0.82g of4-[1-(4-methoxyphenyl)-3-(methylsulfonyl)-1H-pyrazol-5-yl]phenol(P0025). Mass;345(M+1)

[0688] NMR(DMSO-d6,δ);3.32(3H, s), 3.79(3H, s), 6.73(2H, d, J=8.6 Hz),7.01(2H, d, J=8.9 Hz), 7.05(1H, s), 7.08(2H, d, J=8.6 Hz), 7.27(2H, d,J=8.9 Hz), 9.84(1H, s),

[0689] Preparation 26

[0690] To a solution of P0026-0 (5.0g) and imidazole (3.3g) in DMF(40ml) was added portionwise TBDMSC1 (6.69g) at room temperature. Afterstirring overnight, water and hexane was added. The aqueous layer wasseparated and extracted twice with hexane. The combined organic layerwas washed with water (twice) and brine, dried over MgSO4, filtered andevaporated under reduced pressure to give 9.49g (98.3%) of P0026.

[0691] IR (film): 2952.5, 2935.1, 1467.6, 1255.4, 1124.3, 1097.3, 838.9,777.2 cm−1.

[0692] Preparation 27

[0693] To a solution of P0027-0 (10g) and dimethylcarbonate 5.97g in DMFwas added sodium methoxide 4.77g. The mixture was stirred at ambienttemperature for 2hours. The mixture was poured into water with 8 ml ofconc. HCl, and extracted with AcOEt. The organic layer was dried overmagnesium sulfate, and concentrated in vacuo. The residue was purifiedbysilica gel column chromatography to give orange solid. Which wasrecrystallized from MeOH to give P0027 as white crystals.

[0694] NMR (200 MHz, CDCl3) 3.75(3H, s), 3.96(2H, s), 5.14(2H, s),7.02(2H, d, J=8.9 Hz), 7.34-7.45(5H, m), 7.93(2H, d, J=8.9 Hz) Mass ESI285(M+H)+ (file platform 7366-1)

[0695] Preparation 28

[0696] To a solution of triphenylphosphin oxide 294mg in1,2-dichloroethane 3ml was added trifluoromethanesulfonic anhydride198mg dropwise under cooling in an ice bath. The mixture was stirred atsame temperature for 15minutes, when white precipitates were came out.To this mixture was added P0027 (300mg) in 1,2-dichloroethane 2mldropwise, followed by addition of Et3N214mg. The mixture was refluxedfor 2hours. The mixture was allowed to cool to ambient temperature andwas washed with H2O, sat.aq NaCl, dried over MgSO4, concentrated invacuo. The residue was purified by silica gel column chromatographyeluted with AcOEt/n-hexane=5%, and 10%. The residue was crystallizedfrom IPE to give P0028 (166mg) as a white powder.

[0697] Mass (ESI+) : 289 (M+Na)+ 200MHz1HNMR (DMSO-d6, d) : 3.76(3H, s),5.18(2H, s), 7.11(2H, d, J=8.8 Hz), 7.33-7.48(5H, m), 7.62(2H, d, J=8.8Hz)

[0698] Preparation 29

[0699] Solid KOH 124mg was dissolved in EtOH 5ml at 50° C. To thissolution was added P0028 (196mg). After stirring at same temperature for2hours, the reaction mixture was allowed to cool to ambient temperature.The mixture was partitioned between 1M HCl and CHC13. The aqueous layerwas reextracted with CHC13. The combined organic layers were dried overMgSO4, evaporated in vacuo. The residual crystals were collected andwashed with IPE to give 1st crop of P0029 (87mg) as a white powder. Themother liqour was concentrated in vacuo and the residual crystals werecollected and washed with n-hexane to give 2nd crop of P0029 (39mg) as aslightly reddish powder.

[0700] Mass (ESI−) : 251 (M-H)+200MHz 1H NMR (CDC13, d) : 5.10(3H, s),6.97(2H, d, J=8.9 Hz), 7.34-7.43(5H, m), 7.56(2H, d, J=8.9 Hz)

[0701] Preparation 30

[0702] To a solution of P0030-0 (2g) and triethylphosphonoacetate 2.32gin DMF 20ml was added 60% NaH 490mg in two portions with cooling on icebath. The mixture was stirred at same temperature for 1hour, and thenpoured into ice water containing NH4Cl. The mixture was stirred for awhile, and white precipitates were collected and washed with water and10% aqueous IPA to give P0030.

[0703] 200MHz 1H NMR (CDC13, d) : 1.33(3H, t, J=7.2 Hz), 4.25(2H, q,J=7.2 Hz), 5.10(2H, s), 6.31(1H, d, J=16.0 Hz), 6.97(2H, d, J=8.7 Hz),7.32-7.50(7H, m), 7.64(1H, d, J=16.0 Hz)

[0704] Preparation 31

[0705] To a solution of P0030 (2.79g) in CH2C1228ml was added bromine1.66g dropwise under ice bath cooling. The mixture was stirred at sametemperature for 30minutes. The reaction mixture was poured into 5%aqueous solution of Na2S2O3, and partitioned. The organic layer waswashed with sat.aq NaHCO3, sat.aqNaC1, dried over MgSO4, concentrated invacuo. The residual crystals were collected and washed with n-hexane togive P0031 (3.07g) as a pale yellow powder. 200MHz 1H NMR (CDCl3, d) :1.38(3H, t, J=7.2 Hz), 4.35(2H, q, J=7.2 Hz), 4.81(1H, d, J=ll.8 Hz),5.07(2H, s), 5.35(1H, d, J=1l.8 Hz), 6.98 (2H, d, J=8.7 Hz), 7.34 (2H,d, J=8.7 Hz), 7.32-7.45(5H, m)

[0706] Preparation 32

[0707] 85% solid KOH 1.73g was dissolved in 95% aqueous EtOH 20ml at 50°C. P0031 (3.05g) was added in one portion and the mixture was refluxedfor 9hours. To this mixture was added a solution of 85% KOH 0.32gdissolved in 95% aqueous EtOH 10ml and refluxed for 5hours. The mixturewas cooled in an ice bath, precipitates were collected and washed withEtOH. The crystals were suspended in AcOEt and H2O, cooled in an icebath, acidified by 3M HCl and 1M HCl. The mixture was partitioned andthe organic layer was washed with H2O, dried over MgSO4, concentrated invacuo. The residual solid was collected andwashedwith IPE-n-hexane togive P0032 (0.67g) as a white powder.

[0708] 200MHz 1H NMR (CDC13, d) : 5.10(3H, s), 6.97(2H, d, J=8.9 Hz),7.34-7.43(5H, m), 7.56(2H, d, J=8.9 Hz)

[0709] Example 102

[0710] To a solution of P0032(99.9mg) and HOBT 64.2mg inN-methylpyrrolidone 1ml was added WSCD-HCl 91.1mg and the mixture wasstirred at ambient temperature for 20minutes. In another flask,diisopropylethylamine 76.8mg was added to a suspension of E0102-0(83.0mg) in N-methylpyrrolidone 1ml and stirred at ambient temperatureuntil all E0102-0 was dissolved. The solution of E0102-0 was added tothe reaction flask and the mixture was stirred at ambient temperaturefor 1hour. The mixture was partitioned between AcOEt and H2O, washedwith sat.aqNaHCO3, sat.aqNaC1, dried over MgSO4, and concentrated invacuo. The residue was dissolved in CH2C12 3ml, and stirred at ambienttemperature for 24hours. The mixture was concentrated in vacuo. Theresidual crystals were suspended in hot AcOEt, cooled with stirring,collected and washed with AcOEt to give E0102 (90.9mg) as a whitepowder.

[0711] Mass (ESI+) : 373 (M+H)+200MHz1HNMR (DMSO-d6, d): 3.75(3H, s) ,5.08(2H, s) , 5.81(1H, s), 6.90(2H, d, J=9.0 Hz), 6.96(2H, d, J=9.0 Hz),7.10(2H, d, J=9.0 Hz), 7.12(2H, d, J=9.0 Hz), 7.32-7.47(5H, m),10.00(1H, s)

[0712] Example 103

[0713] To a suspension of E0102 (20.9mg) and K2CO3 23.3mg in DMSO 0.5mlwas added dimethylsulfate 10.6mg and the mixture was stirred at ambienttemperature for 1hour. The mixture was partitioned between AcOEt andH2O, and the organic layer was washed with sat.aqNaC1, dried over MgSO4,concentrated in vacuo. The residue was purified by preparative thinlayer chromatography developed with AcOEt/n-hexane=25%. The obtainedcrystals were crystallized from IPE to give E0103 (12.0mg) as whitecrystals.

[0714] Mass (ESI+) : 387 (M+H)+200MHz1HNMR (DMSO-d6, d) : 3.76(3H, s),3.83(3H, s), 5.08(2H, s), 6.04(1H, s), 6.92(2H, d, J=9.0 Hz), 6.97(2H,d, J=9.0 Hz), 7.11-7.17(4H, m), 7.30-7.50(5H, m) 200MHz1HNMR (CDC13, d):3.80(3H, s), 3.97(3H, s), 5.04(2H, s), 5.88(1H, s), 6.82(2H, d, J=9.0Hz), 6.88(2H, d, J=8.9 Hz), 7.11-7.21(4H, m), 7.34-7.43(5H, m)

[0715] Example 104

[0716] To suspension of E0102 (818mg) and K2C03 911mg in DMF 6ml wasadded dimethylcarbonate 0.56ml. The mixture was stirred at 120° C. for2hours. Additional dimethylcarbonate lml was added and stirred at 120°C. for 8hours. The mixture was partitioned between AcOEt and H2O, andthe aq layer was reextracted with AcOEt. The combined organic layerswere washed with sat.aqNaC1, dried over MgSO4, concentrated in vacuo.The residue was purified by silica gel column chromatography eluted withAcOEt/n-hexane=30%. The residue was crystallized from AcOEt 2.5ml andn-hexane 5ml to give E0104 (583mg) as white crystals.

[0717] 200MHz1HNMR (DMSO-d6, d) : 3.76(3H, s), 3.83(3H, s), 5.08(2H, s),6.04(1H, s), 6.92(2H, d, J=9.0 Hz), 6.97(2H, d, J=9.0 Hz), 7.11-7.17(4H,m), 7.30-7.50(5H, m)

[0718] 200MHz1HNMR (CDC13, d) :3.80(3H, s), 3.97(3H, s), 5.04(2H, s),5.88(1H, s), 6.82(2H, d, J=9.0 Hz), 6.88(2H, d, J=8.9 Hz), 7.11-7.21(4H,m), 7.34-7.43(5H, m)

[0719] Preparation 33

[0720] A mixture of 10% Pd-C 50% wet 50mg and E0104 (261mg) in AcOEt 2mland MeOH 2ml was hydrogenated under H2 latm at ambient temperature for1day. The additional 10% Pd-C 50% wet 50mg was added and the mixture washydrogenated under H2 3.5atm at ambient temperature for 3hours. Thecatalyst was filtered off and the filtrate and combined washings wereconcentrated in vacuo. The residue was dissolved in AcOEt, dried overMgSO4, and concentrated in vacuo. The residue was crystallized fromAcOEt-n-hexane to give P0033 (146mg) as a white powder.

[0721] Mass (ESI+) : 297 (M+H)+200MHz1HNMR (DMSO-d6, d) : 3.75(3H, s),3.83(3H, s), 5.98(1H, s), 6.70(2H, d, J=8.6 Hz), 6.91(2H, d, J=8.9 Hz),7.01(2H, d, J=8.6 Hz), 7.12(2H, d, J=8.9 Hz), 9.69(1H, s)

[0722] Preparation 34

[0723] To a solution of ammmonium formate 455mg in H2O 1ml was addedEtOH 6ml, E0104 (558mg), THF 1m1, and 10% Pd-C 50% wet 60mgsuccessively. The mixture was refluxed for 1hour. The catalyst wasremoved by filtration. The filtrate and combined washings wereconcentrated in vacuo. The residue was partitioned between AcOEt andH2O, and the organic layer was washed with sat.aqNaC1, dried over MgSO4,concentrated in vacuo. The residual crystals were recrystallized fromAcOEt 3ml and n-hexane 3ml to give P0034 (335mg) as white crystals.

[0724] Mass (ESI+) 297 (M+H)+

[0725] Example 105

[0726] A mixture of P0003 (2.9g) and 4-methoxyphenylhydrazine (1.68g)inaceticacid (30ml) was stirred at room temperature for 15 hours. Afteraddition of water, the mixture was extracted twice with toluene. Thecombined organic layer was washed with water (twice), sat.NaHCO3, waterand brine, dried over MgSO4, filtered and evaporated under reducedpressure. The residue was column chromatographed on silica gel (Hex/EtOAc =8:1-4:1) to give 2.2g (57%) of E0105 as an oil.

[0727] IR (film): 1737.6, 1511.9, 1240.0, 1159.0, 1130.1 cm−1.

[0728] Example 106

[0729] E0106 was prepared from P0004 in a similar manner to that ofE0105.

[0730] Mass (ESI+) : 420 (M+H)+200MHz 1H NMR (DMSO-d6, d) :1.79-1.94(2H, m), 1.98(3H, s),2.60-2.68(2H,m),3.88(3H,s),3.98(2H,t,J=6.5Hz), 6.92(1H, d, J=8.9 Hz),7.18(1H, s), 7.24(4H, s), 7.75(1H, dd, J=2.7,8.9 Hz), 8.48(1H, d, J=2.7Hz)

[0731] Example 107

[0732] E0107 (175.7mg) was prepared from P0007 (590mg) and4-methoxyphenylhydrazine hydrochloride (332mg) in a similar manner tothat of E0105.

[0733] Mass (ESI+) : 455 (M+H)+200MHz 1H NMR (DMSO-d6, d) : 1.96(3H, s),2.88(2H, t, J=6.8 Hz), 3.79(3H, s), 4.20(2H, t, J=6.8 Hz), 6.99(2H, d,J=8.9 Hz), 7.15(1H, s), 7.17-7.30(6H, m)

[0734] Example 108

[0735] E0108 was prepared from P0007 in a similar manner to that ofE0105.

[0736] Mass (API-ES positive) 456 (M+H)+, 478 (M+Na)+200MHz 1H NMR(DMSO-d6, d) : 1.96(3H, s), 2.89(2H, t, J=6.8 Hz), 3.88(3H, s), 4.21(2H,t, J=6.8 Hz), 6.92(1H, d, J=8.8 Hz), 7.15-7.35(4H, m), 7.21(1H, s),7.76(1H, dd, J=2.7,8.8 Hz), 8.17(1H, d, J=2.7 Hz)

[0737] Example 109

[0738] E0109 was prepared in a similar manner to that of E0105. Mass(ESI+) 409(M+H)+, 431(M+Na)+

[0739] NMR: SE20.059 200MHz 1H NMR (DMSO-d6, d) : 1.31(3H, t, J=7.1 Hz),1.96(3H, s), 2.87(2H, t, J=6.8Hz), 3.79(3H, s), 4.20(2H, t, J=6.8 Hz),4.32(2H, q, J=7.1 Hz), 6.99(2H, d, J=9.0 Hz), 7.08(1H, s), 7.16-7.28(6H,m)

[0740] Example 110

[0741] E0110 was prepared in a similar manner to that of E0105. Mass(ESI+) : 410 (M+H)+

[0742] 200MHz1HNMR (DMSO-d6, d) : 1.32(3H, t, J=7.1 Hz), 1.96(3H, s),2.89(2H, t, J=6.8 Hz), 3.88(3H, s), 4.21(2H, t, J=-6.8 Hz), 4.33(2H, q,J=7.1 Hz), 6.92(1H, d, J=8.8 Hz), 7.12(1H, s), 7.19-7.32(4H, m),7.73(1H, dd, J=2.7,8.8 Hz), 8.14(1H, d, J=2.7 Hz)

[0743] Example 111

[0744] E0111 was prepared in a similar manner to that of E0105.

[0745] Mass (API-ES positive) : 406(M+H)+, 428(M+Na)+200MHz 1H NMR(DMSO-d6, d) 1.96(3H, s), 2.89(2H, t, J=6.7 Hz), 3.88(3H, s), 4.21(2H,t, J=6.7 Hz), 6.92(1H, d, J=8.8 Hz), 7.20(1H, s), 7.24(2H, d, J=8.7 Hz),7.30(2H, d, J=8.7 Hz), 7.76(1H, dd, J=2.7, 8.8 Hz), 8.18(1H, d, J=2.7Hz)

[0746] Example 112

[0747] E0112 was obtained according to a similar manner to that ofE0105.

[0748] Example 113

[0749] E0113 was obtained according to a similar manner to that ofE0105.

[0750] Example 114

[0751] E0114 was obtained according to a similar manner to that ofE0105.

[0752] Example 115

[0753] E0115 was obtained according to a similar manner to that ofE0105.

[0754] Example 116

[0755] E0116 was obtained according to a similar manner to that ofE0105.

[0756] Example 117

[0757] E0117 was obtained according to a similar manner to that ofE0105.

[0758] Example 118

[0759] A mixture of E0105 (2.0g) and 1N NaOH (15ml) in THF (40ml) wasstirred at room temperature for 5 hours. After the reaction wascompleted, the mixture was neutralized with 1N HCl (15ml), extractedtwice with ethylacetate, washed with 1N HCl, sat.NaHCO3, and brine,dried over NA2SO4, filtered and evaporated under reduced pressure. Theresidue was column chromatographed on silica gel (H/EA =2:1-1:1) to give1.14g (64%) of E0118 as a crystal. mp: 103-104° C. IR (film): 3396.0,1513.9, 1467.6, 1238.1, 1160.9, 1132.0 cm−1.

[0760] Example 119

[0761] E0119 was prepared from E0217 in a similar manner to that ofE0118.

[0762] IR (neat) : 3359, 3332, 3325, 1658, 1651, 1624, 1614, 1545, 1533,1500 cm−1 Mass (ESI+) : 421 (M+H)+

[0763] 200MHz1HNMR (DMSO-d6, d) : 2.71-2.79(2H, m), 3.28-3.39(2H, m),3.76(2H, brs), 3.88(3H, s), 5.47(1H, br), 6.92(1H, d, J=8.9 Hz),7.18(1H, s.), 7.24(4H, s), 7.74(1H, dd, J=2.7, 8.9 Hz), 7.80(1H, t,J=5.9 Hz), 8.19(1H, d, J=2.7 Hz)

[0764] Example 120

[0765] E0120 was prepared-from E0002 in a similar manner to that ofE0118.

[0766] IR (neat) : 3433, 3423, 3398, 3367, 2945, 1612, 1500cm-1 Mass(ESI+) : 378 (M+H)+200MHz 1H NMR (DMSO-d6, d) :1.62-1.77 (2H, m) ,2.57-3.65 (2H, m), 3.34-3.44(2H, m), 3.88(3H, s), 4.48(1H, t, J=5.1 Hz),6.92(1H, d, J=8.9 Hz), 7.17(1H, s), 7.23(4H, s), 7.76(1H, dd, J=8.9,2.8Hz), 8.18(1H, d, J=2.8 Hz)

[0767] Example 121

[0768] E0121 was prepared from E0268 in a similar manner to that ofE0118. white powder mp. 91-92° C.

[0769] IR (KBr) : 3491, 3471, 3437, 2941, 2239, 1610, 1508cm−1 Mass(ESI+) : 336 (M+H)+200MHz 1H NMR (DMSO-d6, d) 3.65-3.73(2H, m), 3.79(3H,s), 3.95-4.05(2H, m), 4.87(1H, t, J=5.4 Hz), 6.93(2H, d, J=8.8 Hz),7.00(2H, d, J=9.0 Hz), 7.16(2H, d, J=8.8 Hz), 7.28(2H, d, J=9.0 Hz),7.32(1H, s)

[0770] Example 122

[0771] E0122 was prepared from E0353 in a similar manner to that ofE0118. white powder mp. 158-159° C.

[0772] IR (KBr) : 3399, 2955, 1707, 1693, 1647, 1614, 1566, 1547, 1529,1512 cm−1

[0773] Mass (ESI+) : 393 (M+H)+

[0774] 200MHz 1H NMR (DMSO-d6, d) : 2.44(3H, s), 3.66-3.74(2H, m),3.80(3H,s),3.96-4.02(2H,m), 4.88(1H,t,J=5.4Hz), 6.94(2H, d, J=8.7 Hz),7.02(2H, d, J=8.9 Hz), 7.22(2H, d, J=8.7 Hz), 7.26(1H, s), 7.31(2H, d,J=8.9 Hz)

[0775] Example 123

[0776] E0123 was prepared from E0358 in a similar manner to that ofE0118. white powder mp. 105-107° C.

[0777] IR (KBr) : 3529, 3437, 2956, 1610, 1570, 1547, 1529cm−1

[0778] Mass (ESI+) : 337 (M+H)+

[0779] 200MHz 1H NMR (DMSO-d6, d) : 3.65-3.73(2H, m), 3.88(3H, s),3.96-4.02(2H, m), 4.87(1H, t, J=5.3 Hz), 6.93(1H, d, J=8.8 Hz), 6.96(2H,d, J=8.7 Hz), 7.21(2H, d, J=8.7 Hz), 7.35(1H, s), 7.73(1H, dd, J=2.7,8.8Hz), 8.20(1H, d, J=2.7 Hz)

[0780] Example 124

[0781] E0124 was prepared from E0107 in a similar manner to that ofE0118. white powder mp. 97-98° C.

[0782] IR (KBr) : 3427, 2960, 1608, 1516cm−1

[0783] Mass (ESI+) : 413 (M+H)+200MHz 1H NMR (DMSO-d6, d) : 2.71(2H, t,J=6.9 Hz), 3.54-3.65(2H,m),3.79(3H,s),4.64(1H,t,J=5.1Hz),7.00(2H, d,J=9.0 Hz), 7.12(1H, s), 7.15-7.33(4H, m), 7.29(2H, d, J=9.0 Hz)

[0784] Example 125

[0785] E0125 was prepared in a similar manner to that of E0118.

[0786] IR (neat) : 3435, 3425, 3406, 3398, 3367, 1691, 1658, 1647, 1614,1547, 1512 cm−1

[0787] Mass (ESI+) : 320 (M+H)+, 361(M+CH3CN+H)+200MHz 1H NMR (DMSO-d6,d) 2.71(2H, t, J=6.8 Hz), 3.54-3.64(2H,m),3.79(3H,s),4.64(1H,t,J=5.2Hz),7.00(2H, d, J=8.9 Hz), 7.15(2H, d, J=8.3 Hz),7.23(2H, d, J=8.3 Hz), 7.29(2H, d, J=8.9 Hz), 7.34(1H, s)

[0788] Example 126

[0789] E0126 was prepared from E0111 in a similar manner to that ofE0118. white powder mp. 89-92° C.

[0790] IR (KBr) : 3481, 2947, 1608, 1496cm−1

[0791] Mass (ESI+) : 364 (M+H)+

[0792] 200MHz 1H NMR (DMSO-d6, d) : 2.72(2H, t, J=6.8 Hz),3.55-3.65(2H,m),3.88(3H,s),4.65(1H,t,J=5.2Hz), 6.92(1H, d, J=8.8 Hz),7.16(1H, s), 7.19-7.28(4H, m), 7.77(1H, dd, J=2.6,8.8 Hz), 8.19(1H, d,J=2.6 Hz)

[0793] Example 127

[0794] E0127 was prepared from E0108 in a similar manner to that ofE0118.

[0795] IR (neat) : 3400, 2951, 1610, 1502cm−1 Mass (API-ES positive) :414 (M+H)+, 436 (M+Na)+

[0796] 200MHz 1H NMR (DMSO-d6, d) : 2.72(2H, t, J=6.9 Hz),3.51-3.65(2H,m),3.88(3H,s),4.65(1H,t,J=5.1Hz), 6.93(1H, d, J=8.8 Hz),7.15-7.35(4H, m), 7.18(1H, s), 7.77(1H, dd, J=2.7,8.8 Hz), 8.18(1H, d,J=2.7 Hz)

[0797] Example 128

[0798] E0128 104.4mg was prepared in a similar manner to that of E0118.

[0799] IR (neat) : 3433, 3423, 3398, 2947, 2873, 2243, 1608cm−1 Mass(ESI+) : 321 (M+H)+

[0800] 200MHz 1H NMR (DMSO-d6, d) : 2.72(2H, t, J=6.8 Hz),3.55-3.65(2H,m),3.88(3H,s), 4.65(1H,t,J=5.1Hz), 6.93(1H, d, J=8.8 Hz),7.19(2H, d, J=8.4 Hz), 7.26(2H, d, J=8.4 Hz), 7.38(1H, s), 7.76(1H, dd,J=2.7,8.8 Hz), 8.21(1H, d, J=2.7 Hz)

[0801] Example 129

[0802] E0129 was obtained according to a similar manner to that ofE0118.

[0803] Example 130

[0804] E0130 was obtained according to a similar manner to that ofE0118.

[0805] Example 131

[0806] E0131 was obtained according to a similar manner to that ofE0118.

[0807] Example 132

[0808] E0132 was obtained according to a similar manner to that ofE0118.

[0809] IR (film): 3392.2, 1494.6, 1236.2, 1160.9, 1133.9, 1095.4, 975.8,833.1 cm−1.

[0810] Example 133

[0811] E0133 was obtained according to a similar manner to that ofE0118.

[0812] IR (film): 3374.8, 1511.9, 1471.4, 1274.7, 1232.3, 1160.9,1133.9, 977.7, 842.7, 811.9 cm−1. mp: 82-83 ° C.

[0813] Example 134

[0814] E0134 was obtained according to a similar manner to that ofE0118.

[0815] IR (film): 3386.4, 1511.9, 1471.4, 1236.2, 1159.0, 1132.0,1047.2, 975.8, 817.7 cm−1.

[0816] Example 135

[0817] E0135 was obtained according to a similar manner to that ofE0118.

[0818] IR (film): 3399.9, 1610.3, 1513.9, 1459.9, 1251.6, 1172.5,1083.8, 1033.7, 836.9, 802.2 cm−1. (FS7081)

[0819] Example 136

[0820] P0018 (277mg) and 4-methoxyphenylhydrazine hydrochloride (209mg)in EtOH:AcOH=20:1 6ml was refluxed for 2hours. The mixture waspartitioned between AcOEt and H2O. The organic layer was washedsuccessively with 1M HCl, saturated aqueous sodium bicarbonate solution,and saturated aqueous sodium chloride solution, dried over magnesiumsulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography eluted with AcOEt/n-hexane =30%, 40%, 50%.Thepure fraction was collected and concentrated in vacuo. The residuewas crystallized from AcOEt/n-hexane to give E0136 (95.6mg) as a whitepowder. mp. 111-112° C.

[0821] IR (KBr) : 3325, 2931, 1707, 1693, 1685, 1658, 1647, 1564, 1549,1514 cm−1 Mass (ESI+) 335 (M+H)+

[0822] 200MHz 1H NMR (DMSO-d6, d) :0.69-0.77 (2H, m) , 0.86-0.96 (2H,m), 1.93(1H, m), 2.69(2H, t, J=6.9 Hz), 3.53-3.64(2H, m), 3.76(3H, s),4.64(1H, t, J=5.2 Hz), 6.28(1H, s), 6.92(2H, d, J=9.0 Hz), 7.05-7.19(6H,m)

[0823] Example 137

[0824] E0137 was prepared from P0018 498.5mg in a similar manner to thatof E0136.

[0825] Preparation 34

[0826] P0034 was prepared in a similar manner to that of E0137. whitepowder

[0827] Mass (ESI+) : 306 (M+H)+200MHz 1H NMR (DMSO-d6, d) 0.67-0.76 (2H,m), 0.84-0.94(2H, m), 1.91(1H, m), 3.76(3H, s), 6.18(1H, s), 6.68(2H, d,J=8.7 Hz), 6.91(2H, d, J=9.0 Hz), 6.98(2H, d, J=8.7 Hz), 7.12(2H, d,J=9.0 Hz), 9.63(1H, s)

[0828] Example 138

[0829] To a solution of E0118 (1.0g) and Et3N (0.6ml) in CH2C12 (20ml)was added dropwise methanesulfonyl chloride (0.26ml) under ice-cooling.After stirring for 1 hour, the reaction mixture was quenched with waterand extracted with CHC13. The organic layer was washed with water, driedover Na2SO4, filtered and evaporated to give 1.2g (99%) of crude E0138as an off-white solid.

[0830] IR (film) : 1513.9, 1469.5, 1351.9, 1240.0, 1166.7, 1130.1,971.9, 835.0, 804.2 cm−1.

[0831] Example 139

[0832] E0139 was prepared in a similar manner to that of E00138. Mass(ESI+) : 459 (M+H)+200MHz 1H NMR (DMSO-d6, d)

[0833] 1.09-1.23(3H, m), 2.98,3.29(3H, s), 3.01(2H, t, J=6.6 Hz),3.09(3H, s), 3.43-3.77 (2H, m) , 3.87 (3H, s), 4.42 (2H, t, J=6.6 Hz),6.88-6.92(2H, m), 7.25(2H, d, J=8..3 Hz), 7.33(2H, d, J=8.3 Hz),7.65-7.73(1H, m), 8.15(1H, d, J=2.6 Hz)

[0834] Example 140

[0835] E0140 was prepared in a similar manner to that of E0138. Mass(APCI+) : 458 (M+H)+

[0836] 200MHz1HNMR (DMSO-d6,d) :1.05-1.25(3H,m), 2.96-3.03(2H,m),2.98,3.29(3H,s),3.08(3H, s),3.40-3.85(2H,m), 3.78(3H, s), 4.42(2H, t,J=6.6 Hz), 6.86,6.88(1H, s), 6.98(2H, d, J=8.9 Hz), 7.18-7.32(6H, m)

[0837] Example 141

[0838] E0141 was prepared in a similar manner to that of E0138. Mass(ESI+) : 456 (M+H)+

[0839] 200MHz1HNMR (DMSO-d6, d) :1.89-2.04(2H, m), 2.52-2.73(2H, m),3.16(3H, s), 3.88(3H, s), 4.19(2H, t, J=6.3Hz), 6.92(1H, d, J=8.9 Hz),7.18(1H, s), 7.21-7.31(4H, m), 7.76(1H, dd, J=2.6,8.9 Hz), 8.19(1H, d,J=2.6 Hz)

[0840] Example 142

[0841] E0142 was obtained according to a similar manner to that ofE0138.

[0842] Example 143

[0843] E0143 was obtained according to a similar manner to that ofE0138.

[0844] Example 144

[0845] This compound was obtained according to a similar manner to thatof E0138.

[0846] Example 145

[0847] This compound was obtained according to a similar manner to thatof E0138.

[0848] Example 146

[0849] This compound was obtained according to a similar manner to thatof E0138.

[0850] Example 147

[0851] This compound was obtained according to a similar manner to thatof E0138.

[0852] Example 148

[0853] A mixture of E0138 (900mg) and potassium phthalimide (454mg) inDMF (18ml) was stirred at 60° C. for 3.0 hours. After addition of water,the reaction mixture was extracted with EtOAc and washed twice withwater and with brine. The organic layer was dried over Na2SO4 , filteredand evaporated under reduced pressure. The residue was columnchromatographed on silica gel (50ml) to give 930mg (93%) of E0148 as apowder.

[0854] IR (film): 1772.3, 1712.5, 1240.0, 1160.9, 1130.1cm−1.

[0855] Example 149

[0856] E0149 was prepared from E0139 in a similar manner to that ofE0148. amorphous powder Mass (ESI+) : 510 (M+H)+

[0857] 200MHz 1H NMR (DMSO-d6, d) 1.08-1.22(3H, m), 2.89-2.98(2H, m),2.98,3.27(3H, s), 3.48,3.70(2H, q, J=7.1,6.9 Hz), 3.82(2H, t, J=7.3 Hz),3.88(3H,s), 6.83-6.88(2H,m),7.23(2H,d,J=8.7Hz),7.18(2H, d, J=8.7 Hz),7.53-7.63(1H, m), 7.79-7.89(4H, m), 8.15(1H, d, J=2.6 Hz)

[0858] Example 150

[0859] E0150 was prepared from E0140 in a similar manner to that ofE0148. amorphous powder Mass (ESI+) : 509 (M+H)+

[0860] 200MHz 1H NMR (DMSO-d6, d) : 1.12,1.18(3H, t, J=7.0,7.1 Hz),2.92(2H, t, J=7.0Hz), 2.97,3.28(3H, s), 3.47,3.71(2H, q, J=7.1,7.0 Hz),3.78(3H, s), 3.81(2H, t, J=7.0 Hz), 6.82,6.84(1H, s), 6.94(2H, d, J=9.0Hz), 7.11-7.20(6H, m), 7.79-7.89(4H, m)

[0861] Example 151

[0862] E0151 was prepared from E0038 in a similar manner to that ofE0148.

[0863] Mass (ESI+) : 507 (M+H)+200MHz1HNMR (DMSO-d6, d) : 1.82-1.97(2H,m), 2.59-2.67(2H, m), 3.60(2H, t, J=7.0 Hz), 3.88(3H, s), 6.91(1H, d,J=8.8 Hz), 7.14(1H, s), 7.20(2H, d, J=8.5 Hz), 7.26(2H, d, J=8.5 Hz),7.73(1H, dd, J=8.8,2.8 Hz), 7.78-7.89(4H, m), 8.17(1H, d, J=2.8 Hz)

[0864] Example 152

[0865] This compound was obtained according to a similar manner to thatof E0148.

[0866] Example 153

[0867] This compound was obtained according to a similar manner to thatof E0148.

[0868] Example 154

[0869] This compound was obtained according to a similar manner to thatof E0148.

[0870] Example 155

[0871] This compound was obtained according to a similar manner to thatof E0148.

[0872] Example 156

[0873] This compound was obtained according to a similar manner to thatof E0148.

[0874] Example 157

[0875] This compound was obtained according to a similar manner to thatof E0148.

[0876] Example 158

[0877] To a solution of E0148 (800mg) in CH3CN (10ml) was addedhydrazine hydroxide (87ul) at room temperature. After stirring for 1hour, the reaction mixture was filtered and evaporated. After additionof dichloromethane, the mixture was stirred for an hour, filtered andevaporated. The residue was treated with 4NHCl/EtOAc to give 518mg (80%)of E0158.

[0878] IR (Film); 3403.74, 1610.27, 1511.92, 1467.56, 1238.08, 1160.94,1130.08, 1027.87, 975.80, 836.96, 806.10 cm−1.

[0879] Example 159

[0880] This compound was obtained according to a similar manner to thatof E0158.

[0881] Example 160

[0882] This compound was obtained according to a similar manner to thatof E0158.

[0883] Example 161

[0884] This compound was obtained according to a similar manner to thatof E00158.

[0885] IR (film): 3428.8, 1511.9, 1467.6, 1238.1, 1160.9, 1132.0cm−1.

[0886] Example 162

[0887] This compound was obtained according to a similar manner to thatof E0158.

[0888] IR (film) : 3371.0, 1511.9, 1471.4, 1272.8, 1230.4, 1160.9,1133.9, 975.8, 842.7, 810.0 cm−1.

[0889] Example 163

[0890] This compound was obtained according to a similar manner to thatof E0158. mp: 163.1-165.1° C.

[0891] IR (film): 2973.7, 1511.9, 1471.4, 1236.2, 1159.0, 1133.9cm−1.

[0892] Example 164

[0893] This compound was obtained according to a similar manner to thatof E0158.

[0894] IR(film): 3369.0, 1604.5, 1513.9, 1459.9, 1251.6, 1172.5, 1083.8,1029.8,837.0, 800.3 cm−1.

[0895] Example 165

[0896] To a solution of E0395 (1.08 g) in acetonitril (15 ml) was addedhydrazine monohydrate (0.53 ml). After stirring at 60° C. overnight, themixture was filtered. And the filtrate was evaporatedtogive E0165 asanorange oil (814mg, 102%). NMR(CDC13), 2.76(2H, t, J=6.5 Hz), 2.98(2H,t, J=6.5 Hz), 3.94(3H,s), 6.73(1H,s), 6.76(1H,d,J=8.9Hz),7.22-7.12(4H,m), 7.57(1H, dd, J=8.9, 2.7 Hz), 8.09(1H, d, J=2.7 Hz).MS(ESI+);363.3(MH+).

[0897] Example 166

[0898] E0166 was prepared from E0046 in a similar manner to that ofE0165.

[0899] Mass (ESI+) : 380 (M+H)+200MHz 1H NMR (DMSO-d6, d) 1.91-1.23(3H,m), 2.59-2.79(4H, m), 2.98,3.28(3H, s), 3.48,3.71(2H, q, J=7.2,7.0 Hz),3.87(3H, s), 6.86-6.93(2H, m), 7.16-7.26(4H, m), 7.64-7.73(1H, m),8.15(1H, d, J=2.5 Hz)

[0900] Example 167

[0901] E0167 was prepared from E0150 in a similar manner to that ofE0165.

[0902] Mass (ESI+) 379 (M+H)+200MHz 1H NMR (DMSO-d6, d) 1.08-1.22(3H,m), 2.57-2.78(4H, m), 2.97,3.29(3H, s), 3.48,3.72(2H, q, J=7.2,7.0 Hz),3.78(3H, s), 6.83,6.85(1H, s), 6.98(2H, d, J=8.9 Hz), 7.06-7.26(6H, m)

[0903] Example 168

[0904] E0168 was prepared from E0048 in a similar manner to that ofE0165.

[0905] Mass (ESI+) 377 (M+H)+200MHz1HNMR (DMSO-d6, d) : 1.54-1.69(2H,m),2.49-2.64(4H, m), 3.88(3H, s), 6.92(1H, d, J=8.7Hz), 7.17(1H, s),7.22(4H, s), 7.75(1H, dd, J=8.7,2.6 Hz), 8.18(1H, d, J=2.6 Hz)

[0906] Example 169

[0907] To a solution of E0165 (180 mg) in tetrahydrofuran (2 ml) wasadded triethylamine (0.242 ml) and t-butoxycarbonyl anhydride (325 mg)at room temperature. After stirring at room temperature overnight, themixture was quenched with water and extracted with ethyl acetate (x3).The organic layer was washed with hydrogen chloride aqueous solution(lN), saturated sodium hydrogen carbonate aqueous solution, and brine,dried over magnesium sulfate, and evaporated to giveoil,whichwaspurifiedwith column chromatography (SiO2 25 ml, 20% ethylacetate/hexane) to give E0169 as an oil (224 mg , 97.5%).

[0908] NMR(CDCl3); 1.35(9H, s), 2.69(2H, t, J=7.7 Hz),3.09-3.19(2H,m),3.88(3H,s), 6.91(1H,d,J=8.8Hz),7.17(1H, s),7.18-7.27(4H, m), 7.75(1H, dd, J=8.8, 2.7 Hz), 8.19(1H, d, J=2.7 Hz).MS(ESI+); 485.2(M+Na).

[0909] Example 170

[0910] This compound was obtained according to a similar manner to thatof E0169.

[0911] NMR(CDC13), 1.45(9H, s), 3.49-3.57(2H, m), 3.82(3H, s), 4.01(2H,t, J=5.1 Hz), 6.67(1H, s), 6.82(2H, d, J=8.7 Hz), 6.87(2H, d, J=9.0 Hz),7.13(2H, d, J=8.7 Hz), 7.22(2H, d, J=9.0 Hz). MS(ESI+), 500.2(M+Na).

[0912] Example 171

[0913] A mixture of E0158 (650mg) , Boc2O (428mg) and 1NNaOH (3.3ml) inTHF (20ml) was stirred at room temperature for 15 hours. Water and EtOAcwas added and the aqueous layer was separated and extracted with EtOAc.The combined organic layer was washed with sat NaHCO3, water and brine,dried over NA2SO4, filtered and evaporated under reduced pressure. Theresidue was column chromatographed on silica gel (Hex/EtOAc) to give700mg (93%) of E0171 as an oil.

[0914] Example 172

[0915] This compound was obtained according to a similar manner to thatof E0171.

[0916] Example 173

[0917] This compound was obtained according to a similar manner to thatof E0171.

[0918] Example 174

[0919] This compound was obtained according to a similar manner to thatof E0171.

[0920] IR (film): 1702.8, 1513.9, 1241.9, 1164.8, 1132.0cm−1.

[0921] Example 175

[0922] To a solution of E0171 (200mg) and MeI (0.14ml) in THF (20ml) wasadded portionwise NaH (35mg) at room temperature. Then the reactionmixture was heated at 70° C. for 1 hour. Almost no reaction. MeI (0.3ml)and NaH (40mg) was added, and DMF was added.

[0923] The mixture was stirred at 70° C. for 12 hours, and then cooled,quenched with water. The aqueous layer was extracted twice with EtOAc.The combined organic layer was washed with water and brine, dried overMgSO4, filtered and evaporated. The residue was column chromatographedon silica gel to give 151mg (73%) of E0175 as an oil.

[0924] Example 176

[0925] This compound was obtained according to a similar manner to thatof E0175.

[0926] Example 177

[0927] To a mixture of E0158 (150mg) and HCHO (46ul) in Et3N (53ul) andCH3CN (5ml) was added portionwise NaBH(OAc)2 (240mg) at roomtemperature. After stirring for 15 hours, the mixture was quenched withwater and extracted three times with EtOAc. The combined organic layerwas washed with water and brine, dried over Na2SO4, filtered andevaporated under reduced pressure. The residue was columnchromatographed on silica gel (CHC13/MeOH) and treated with4NHCl/dioxane to give 108mg (70%) of E0177.

[0928] Example 178

[0929] Methylisocyanate 36.2mg was added to a solution of E0165(199.3mg) and triethylamine 48.6mg in CH2C12 2ml under ice bath cooling.The reaction mixture was stirred at same temperature for lhour andconcentrated in vacuo. The residue was partitioned between AcOEt and 1MHCl. The organic layer was washed with saturated aqueous sodiumbicarbonate solution and saturated aqueous sodium chloride solution,dried over magnesium sulfate, and concentrated in vacuo. The residue wasrecrstallized fromAcOEt-n-hexane. Obtained powder was dissolved in CHC13and further purified by preparative thin layer silica gel chromatographydeveloped byMeOH /CHC13=10%. The seaparated silica gel was extractedwith 10% MeOH/CHCl3 and the solvent was evaporated in vacuo. Theresidual solid was collected and washed with diisopropyl ether to giveE0178 (101.3mg) as a white powder. mp. 149° C.

[0930] IR (KBr) : 3348, 2947, 2885, 1626, 1583, 1529, 1500cm−1 Mass(ESI+) : 420 (M+H)+

[0931] 200MHz 1H NMR (DMSO-d6, d) : 2.49-2.53(3H, overlapping),2.64-2.72(2H, m), 3.15-3.26(2H, m), 3.88(3H, s), 5.72(1H, q, J=4.5 Hz),5.89(1H, t, J=5.7 Hz), 6.92(1H, d, J=8.8 Hz), 7.17(1H, s), 7.24(4H, s),7.76(1H, dd, J=2.7, 8.8 Hz), 8.19(1H, d, J=2.7 Hz)

[0932] Example 179

[0933] E0179 80.7mg was prepared from E0166 in a similar manner to thatof E0178. amorphous powder

[0934] IR (neat) : 3350, 2950, 2930, 1707, 1691, 1674, 1645, 1641, 1622,1614, 1566, 1549, 1533, 1510 cm−1 Mass (ESI+) 437 (M+H)+

[0935] 200MHz1HNMR(DMSO-d6,d) 1.09-1.23(3H,m),2.49-2.54(3H,overlapping), 2.67(2H, t, J=7.2 Hz), 2.98,3.28(3H, s), 3.15-3.28(2H, m),3.48,3.71(2H, q, J=6.8,6.9Hz), 3.88(3H, s), 5.73(1H, q, J=4.6 Hz),5.90(1H, t, J=5.6 Hz), 6.86-6.93(2H, m), 7.22(4H, s), 7.64-7.73(1H, m),8.15(1H, d, J=2.6 Hz)

[0936] Example 180

[0937] E0180 was prepared from E0294 in a similar manner to that ofE0178. white powder mp. 155-157° C.

[0938] IR (KBr) :3336, 2968, 1707, 1693, 1674, 1621, 1576, 1533cm−1 Mass(ESI+) : (M+H)+

[0939] 200MHz 1H NMR (DMSO-d6, d) : 0.96(3H, t, J=7.1 Hz), 2.64-2.72(2H,m), 2.91-3.05(2H, m), 3.15-3.26(2H, m), 3.88(3H,s),5.76-5.84(2H,m),6.92(1H,d,J=8.8Hz),7.17(1H, s), 7.24(4H, s), 7.76(1H, dd, J=8.8,2.7 Hz),8.19(1H, d, J=2.7 Hz)

[0940] Example 181

[0941] This compound was obtained according to a similar manner to thatof E0178.

[0942] IR (film): 3343.9, 1658.5, 1608.3, 1513.9, 1457.9, 1249.6,1029.8, 836.9 cm−1.

[0943] Example 182

[0944] This compound was obtained according to a similar manner to thatof E0178.

[0945] IR (Film) : 1659.0, 1608.8, 1554.8, 1485.4, 1470.0, 1240.4,1165.1, 1134.3, 1097.6, 835.3 cm−1.

[0946] Example 183

[0947] This compound was obtained according to a similar manner to thatof E0178.

[0948] IR (film): 3249.8, 1658.5, 1608.3, 1554.3, 1469.5, 1240.0,1164.8, 1133.9, 1097.3, 975.8, 835.0 cm−1.

[0949] Example 184

[0950] AcCl 23.3mg was added to E0158 (107.4mg) and triethylamine 68.3mgin CH2C12 2ml with cooling in an ice bath. After stirring at sametemperature for 1hour, the reaction mixture was concentrated in vacuo.The residue was partitioned between AcOEt and 1M HCl. The organic layerwas washed with saturated aqueous sodiumbicarbonate solution andsaturated aqueous sodium chloride solution, dried over magnesiumsulfate, and concentrated in vacuo. The residual solid were collectedand washed with diisopropyl ether to give E0184 (84mg) as a whitepowder. mp. 79-80° C.

[0951] IR (KBr) :3307, 3221, 3093, 2964, 1689, 1639, 1554, 1514cm−1 Mass(ESI+) : 404 (M+H)+

[0952] 200MHz 1H NMR (DMSO-d6, d) : 1.76(3H, s), 2.65-2.73(2H, m),3.18-3.31(2H,m),3.79(3H,s), 6.99(2H,d,-J=8.9Hz),7.12(1H, s), 7.20(4H,s), 7.28(2H, d, J=8.9 Hz), 7.92(1H, t, J=5.4 Hz)

[0953] Example 185

[0954] E0185 (143.4mg) was prepared from E0232 (155.3mg), methylchloroformate 35.8mg, and triethylamine 105mg in a similar manner tothat of E0184. amorphous powder

[0955] IR (neat) : 3319, 2954, 1718, 1711, 1668, 1660, 1612, 1545, 1533,1500 cm−1 Mass (ESI+) : 178 (M+H)+

[0956] 200MHz1HNMR (DMSO-d6, d) :2.67-2.75(2H, m), 3.22-3.33(2H, m),3.50-3.60(2H, overlapping), 3.53(3H, s), 3.88(3H, s), 6.92(1H, d, J=8.8Hz), 7.18(1H, s), 7.24(4H, s), 7.28(1H, t, J=6 Hz), 7.75(1H, dd,J=2.7,8.8 Hz), 7.94(1H, t, J=5.6 Hz), 8.19(1H, d, J=2.7 Hz)

[0957] Example 186

[0958] E0186 (59.3mg) was prepared from E0158 (96.2mg), methylchloroformate 25.1mg and triethylamine 61.2mg in a similar manner tothat of E0184. mp. 78-80° C.

[0959] IR (KBr) : 3352, 1739, 1695, 1658, 1647, 1549, 1514cm−1 Mass(ESI+) : 420 (M+H)+

[0960] 200MHz1HNMR (DMSO-d6, d) : 2.66-2.74(2H,m), 3.14-3.25(2H, m),3.49(3H,s), 3.79(3H,s), 6.99(2H,d,J=8.9Hz),7.12(1H, s), 7.12-7.32(1H,m), 7.20(4H, s), 7.28(2H, d, J=8.9 Hz)

[0961] Example 187

[0962] E0187 (63.4mg) was prepared from E0165 (113.6mg), acetyl chloride29.5mg, and triethylamine 41.2mg in a similar manner to that of E0184.white powder mp.97-98° C.

[0963] IR (KBr) : 3311, 2956, 1674, 1641, 1543, 1500cm−1 Mass (ESI+) :405 (M+H)+

[0964] 200MHz 1H NMR (DMSO-d6, d) : 1.76(3H, s), 2.66-2.74(2H, m),3.19-3.30(2H,m),3.88(3H,s), 6.92(1H,d,J=8.8Hz),7.18(1H, s), 7.24(4H, s),7.75(1H, dd, J=8.8,2.6 Hz), 7.92(1H, t, J=5.3 Hz), 8.19(1H, d, J=2.6 Hz)

[0965] Example 188

[0966] E0188 was prepared from E0165 in a similar manner to that ofE0184.

[0967] IR (neat) : 3338, 3020, 2951, 1716, 1610, 1527, 1500cm−1 Mass(ESI+) : 421 (M+H)+

[0968] 200MHz1HNMR (DMSO-d6, d) :2.67-2.75(2H, m), 3.14-3.25(2H, m),3.49(3H, s), 3.88(3H, s), 6.92(1H, d, J=8.9 Hz), 7.15-7.35(5H, m),7.18(1H, s), 7.75(1H, dd, J=2.7,8.9 Hz), 8.19(1H, d, J=2.7 Hz)

[0969] Example 189

[0970] E0189 was prepared from E0294 in a similar manner to that ofE0184.

[0971] IR (neat) : 3352, 2939, 1691, 1639, 1533, 1500cm−1 Mass (ESI+) :434 (M+H)+

[0972] 200MHz 1H NMR (DMSO-d6, d) : 2.67-2.74(2H, m), 2.74(6H, s),3.15-3.26(2H,m),3.88(3H,s), 6.34(1H,t,J=5.4Hz), 6.92(1H, d, J=8.9 Hz),7.17(1H, s), 7.23(4H, s), 7.75(1H, dd, J=8.9,2.7 Hz), 8.19(1H, d, J=2.7Hz)

[0973] Example 190

[0974] This compound was obtained according to a similar manner to thatof E0189.

[0975] NMR(CDC13);2.78(3H,d, J=5.0Hz), 3.56-3.64(2H,m), 3.82(3H, s),4.03(2H, t, J=5.1 Hz), 4.2-4.4(1H, m, NH), 4.6-4.9(1H, m, NH), 6.67(1H,s), 6.80-6.91(4H, m), 7.13(2H, d, J=8.8 Hz), 7.22(2H, d, J=9.0 Hz).MS(ESI+). 457.1(M+Na) IR(NBr), 1627.6cm−1

[0976] Example 191

[0977] This compound was obtained according to a similar manner to thatof E0184.

[0978] IR (film): 3299.6, 1658.5, 1550.5, 1515.8, 1467.6, 1240.0,1164.8, 1132.0, 975.8, 829.2, 755.9 cm−1.

[0979] Example 192

[0980] E0158 (250mg) was suspended inAcOEt 5ml and was partitionedbetween AcOEt and saturated aqueous sodium bicarbonate solution. Theorganic layer was washed with aqueous sodium chloride solution, driedover magnesium sulfate, and concentrated in vacuo. The residue wasdissolved in dimethoxyethane 5ml, sulfamide 181mg was added and refluxedfor 2days. The reacion mixture was concentrated in vacuo, and theresidue was purified by silica gel column chromatography eluted withMeOH/CHC13=1%, 2%, then 3%. Obtained amorphous powder was crystallizedfrom EtOH-diisopropyl ehter to give E0192 153mg as a white powder. mp.127-128° C. IR (KBr) : 3357, 1707, 1693, 1647, 1564, 1549, 1529,1514cm−1 Mass (ESI+) : 441 (M+H)+

[0981] 400MHz1HNMR(DMSO-d6,d) :2.76-2.80(2H,m),3.06-3.11(2H, m),3.79(3H,s), 6.53(2H, s), 6.53-6.61(1H,broad),7.00(2H, d, J=8.9 Hz),7.12(1H, s), 7.21(2H, d, J=8.5 Hz), 7.24(2H, d, J=8.5 Hz), 7.29(2H, d,J=8.9 Hz)

[0982] Example 193

[0983] E0193 was prepared from E0294 in a similar manner to that ofE0192. white powder mp.114-115° C.

[0984] IR (KBr) : 3489, 3469, 3458, 3435, 3425, 3398, 3363, 3280, 1647,1500 cm−1 Mass (ESI+) : 442 (M+H)+

[0985] 200MHz1HNMR (DMSO-d6, d) : 2.75-2.83(2H, m)), 3.00-3.20(2H, m),3.88(3H, s), 6.45-6.67(3H, m), 6.92(1H, d, J=8.7 Hz), 7.18(1H, s),7.21-7.31(4H, m), 7.76(1H, dd, J=2.6,8.7 Hz), 8.19(1H, d, J=2.6 Hz)

[0986] Example 194

[0987] E0194 was prepared from E0322 in a similar manner to that ofE0192. white powder mp. 142-143° C. IR (KBr) : 3415, 3323, 3111, 3093,3010, 2962, 1614, 1516cm−1 Mass (ESI+) : 429 (M+H)+

[0988] 200MHz1HNMR(DMSO-d6, d) : 0.68-0.76(2H,m), 0.85-0.95(2H, m),1.92(1H,m), 3.15-3.31(2H,m), 3.76(3H,s), 4.00-4.07(2H, m), 6.25(1H, 1),6.60(2H,brs), 6.72(1H,brs), 6.86-6.96(4H, m), 7.10(2H, d, J=8.7 Hz),7.13(2H, d, J=8.9 Hz)

[0989] Example 195

[0990] This compound was obtained according to a similar manner to thatof E0192.

[0991] NMR(CDC13), 3.50-3.59(2H,m), 3.82(3H, s), 4.14(2H, t, J=4.9 Hz),6.68(1H, s), 6.80-6.90(4H, m), 7.15(2H, d, J=8.8 Hz), 7.22(2H, d, J=9.0Hz). IR(KBr); 1612, 1552cm−1. MS(ESI+), 479.1(M+Na).

[0992] Example 196

[0993] To a solution of E0158 (100mg) and Et3N (53ul) in CHCl3 (10ml)was added MsCl (29ul) at room temperature. After stirring for 1 hour,the reaction mixture was poured onto water and CHCl3. The aqueous layerwas separated and extracted with CHCl3. The combined organic layer waswashed with water and brine, dried over Na2SO4, filtered and evaporatedunder reduced pressure. The residue was column chromatographedon silicagel (50ml) and crystalized to give 75mg (68%) of E0196 as a powder.

[0994] IR (film): 3284.2, 1513.9, 1319.1, 1240.0, 1151.3, 973.9cm−1.

[0995] Example 197

[0996] E0197 was prepared from E0166 in a similar manner to that ofE0196. mp.137-138° C.

[0997] IR (KBr) : 3222, 1691, 1684, 1658, 1645, 1610, 1566, 1547, 1531cm−1 Mass (ESI+) : 458 (M+H)+

[0998] 200MHz 1H NMR (DMSO-d6, d) 1.09-1.22(3H, m), 2.73-2.81(2H, m),2.80(3H, s), 2.98,3.28(3H, s), 3.09-3.30(2H, m), 3.48,3.71(2H, q,J=7.0,6.8Hz),3.87(3H, s), 6.88-6.93(2H,m),7.10(1H,brs), 7.22(2H, d,J=8.5Hz), 7.28(2H, d, J=8.5Hz), 7.64-7.73(1H, m), 8.15(1H, d, J=2.5 Hz)

[0999] Example 198

[1000] E0198 was prepared from E0167 in a similar manner to that ofE0196. mp.162-163° C.

[1001] IR (KBr) : 3224, 1610, 1547, 1512cm−1 Mass (ESI+) : 457 (M+H)+

[1002] 200MHz 1H NMR (DMSO-d6, d) : 1.08-1.22(3H, m), 2.76(2H, t, J=7.2Hz), 2.80(3H, s), 2.98,3.29(3H, s), 3.12-3.23(2H, m), 3.48,3.73(2H, q,J=7.2,6.9 Hz), 3.78(3H, s), 6.84,6.87(1H, s), 6.98(2H, d, J=9.0 Hz),7.09(1H, t, J=5.7 Hz), 7.16-7.26(6H, m)

[1003] Example 199

[1004] E0199 was prepared from E0234 in a similar manner to that ofE0196. white powder, mp. 155° C.

[1005] IR (KBr) : 3265, 2974, 2937, 1682, 1612, 1512cm−1 Mass (ESI+) :458 (M+H)+

[1006] 200MHz 1HNMR (DMSO-d6, d) : 1.15(6H, d, J=6.8 Hz), 2.94(3H, s),3.27-3.36(2H, m), 3.68(1H, m), 3.79(3H, s), 4.03(2H, t, J=5.5 Hz),6.93(2H, d, J=8.8 Hz), 6.98(1H, s), 7.00(2H, d, J=8.9 Hz), 7.19(2H, d,J=8.8 Hz), 7.28(2H, d, J=8.9 Hz), 7.17-7.30(1H, overlapping)

[1007] Example 200

[1008] E0200 was prepared from E0235 in a similar manner to that ofE0196. white powder mp. 149-153° C.

[1009] IR (KBr) : 3321, 1693, 1658, 1647, 1610, 1547, 1510cm−1 Mass(ESI+) : 413 (M+H)+

[1010] 200MHz 1HNMR (DMSO-d6, d) : 2.93(3H, s), 3.27-3.35(2H, m),3.79(3H, s), 4.03(2H, t, J=5.5 Hz), 6.95(2H, d, J=8.7 Hz), 7.01(2H, d,J=9.0 Hz), 7.18(2H, d, J=8.7 Hz), 7.28(2H, d, J=9.0 Hz), 7.31(1H, s),7.15-7.31(1H, overlapping)

[1011] Example 201

[1012] E0201 was prepared from E0294 in a similar manner to that ofE0196.

[1013] IR (neat) : 3298, 2952, 2885, 1612, 1566, 1547, 1529cm−1 Mass(ESI+) : 470 (M+H)+

[1014] 200MHz 1HNMR (DMSO-d6, d): 2.56(6H, s), 2.71-2.79(2H, m),3.07-3.17(2H, m), 3.88(3H, s), 6.92(1H, d, J=8.7 Hz), 7.18(1H, s),7.19-7.30(5H, m), 7.77(1H, dd, J=8.7,2.6 Hz), 8.18(1H, d, J=2.6 Hz)

[1015] Example 202

[1016] E0202 was prepared from E0322 in a similar manner to that ofE0196. white powder mp. 166-168° C.

[1017] IR (KBr) : 3093, 2964, 2873, 2854, 1614, 1516cm−1 Mass (ESI+) :428 (M+H)+

[1018] 200MHz1HNMR (DMSO-d6, d) : 0.68-0.76(2H, m), 0.85-0.95(2H, m),1.92(1H, m), 2.93(3H, s), 3.27-3.36(2H, m), 3.76(3H, s), 3.98-4.04(2H,m), 6.25(1H, s), 6.90(2H, d, J=8.7 Hz), 6.92(2H, d, J=8.9 Hz), 7.11(2H,d, J=8.7 Hz), 7.13(2H, d, J=8.9 Hz), 7.27(1H, t, J=5.8 Hz)

[1019] Example 203

[1020] This compound was obtained according to a similar manner to thatof E00196.

[1021] MS(ESI+); 454.1(MH+).

[1022] IR(KBr); 1612.2, 1515.8cm−1.

[1023] NMR(CDCl3), 3.03(3H, s), 3.51-3.59(2H, m), 3.82(3H, s), 4.10(2H,t, J=4.9 Hz), 6.68(1H, s), 6.82(1H, d, J=8.7 Hz), 6.88(1H, d, J=8.9 Hz),7.15(1H, d, J=8.7 Hz), 7.22(1H, d, J=8.9 Hz).

[1024] Example 204

[1025] This compound was obtained according to a similar manner to thatof E0196.

[1026] NMR(DMSO-d6); 2.80(3H, s), 2.73-2.84(2H,m), 3.13-3.22(2H, m),3.88(3H, s), 6.92(1H, d, J=9.0 Hz), 7.08-7.13(1H, m), 7.19(1H, s),7.22-7.33(4H, m), 7.76(1H, dd, J=9.0, 2.6Hz), 8.19(1H, d, J=2.6 Hz).

[1027] MS(ESI+),463.1(M+Na).

[1028] IR(KBr), 3136, 1614, 1554, 1144cm−1.

[1029] Example 205

[1030] This compound was obtained according to a similar manner to thatof E0196.

[1031] Example 206

[1032] This compound was obtained according to a similar manner to thatof E0196.

[1033] mp: 134.2-134.5° C. IR (film): 3284.2, 1610.3, 1513.9, 1457.9,1321.0, 1251.6, 1151.3, 1083.8, 1031.7, 838.9, 802.2, 757.9 cm−1.

[1034] Example 207

[1035] This compound was obtained according to a similar manner to thatof E00196.

[1036] IR (film): 3286.11, 1606.41, 1513.85, 1457.92, 1319.07, 1251.58,1153.22, 1081.87, 1029.80, 836.955 cm−1.

[1037] Example 208

[1038] This compound was obtained according to a similar manner to thatof E0196.

[1039] IR(film): 3284.2, 1513.9, 1317.1, 1240.0, 1153.2cm−1.

[1040] Example 209

[1041] This compound was obtained according to a similar manner to thatof E0196.

[1042] IR (film): 3286.1, 1511.9, 1321.0, 1230.4, 1155.2, 975.8, 842.7,756.0 cm−1.

[1043] Example 210

[1044] This compound was obtained according to a similar manner to thatof E0196.

[1045] IR (film): 3284.2, 1511.9, 1469.5, 1321.0, 1236.2, 1153.2, 975.8,821.5, 756.0 cm−1.

[1046] Example 211

[1047] This compound was obtained according to a similar manner to thatof E0196.

[1048] IR (film): 3289.9, 1612.2, 1513.9, 1322.9, 1251.6, 1155.1,1085.7, 1029.8, 975.8, 836.9, 796.4 cm−1.

[1049] Example 212

[1050] This compound was obtained according to a similar manner to thatof E0196.

[1051] IR (film): 3266.8, 1612.2, 1469.5, 1321.0, 1240.0, 1153.2,1097.3, 975.8, 835.0 cm−1.

[1052] Example 213

[1053] This compound was obtained according to a similar manner to thatof E0196.

[1054] IR (film) : 3288.0, 1612.2, 1322.9, 1240.0, 1153.2, 975.8, 946.9cm−1.

[1055] Example 214

[1056] A mixture of E0158 (180mg), formic acid (38ul), and WSCD (155mg)in Et3N (0.3ml) and THF (5ml) was stirred at room temperature for 1hour. After addition of water and EtOAc, the aqueous layer was separatedand extracted twice with EtOAc. The combined organic layer was washedwith 1NHC1, sat.NaHCO3, water and brine, dried over Na2SO4, filtered andevaporated under reduced pressure. The residue was columnchromatographed on silica gel (Hex/EtOAc=2:1) to give 136mg (70%) ofE0214 as a powder.

[1057] IR (film): 1670.1, 1513.9, 1238.1, 1160.9, 1130.1cm−1.

[1058] Example 215

[1059] A mixture of E0158 (250mg), BocGly (132mg), WSCD (127mg) and HOBt(110mg) in Et3N (114ul) and CH2Cl2 (30ml) was stirred at roomtemperature. After stirring for 15 hour, the reaction mixture was pouredonto water and CHCl3. The aqueous layer was separated and extracted withCHCl3. The combined organic layer was washed with water and brine, driedover Na2SO4, filtered and evaporated under reduced pressure. The residuewas column chromatographed on silica gel (50ml) and crystalized to give325mg (99%) of E0215 as an oil.

[1060] Example 216

[1061] E0216 was prepared in a similar manner to that of E0215. oil

[1062] IR (neat) : 3431, 3421, 3404, 3400, 2939, 1614, 1570, 1547cm-−1Mass (ESI+) : 381(M+H)+

[1063] 200MHz 1H NMR (DMSO-d6, d) 1.09-1.23(3H, m), 2.72(2H, t, J=6.9Hz), 2.98,3.29(3H, s), 3.42-3.77(4H, m), 3.88(3H, s), 6.86-6.93(2H, m),7.19(2H, d, J=8.5 Hz), 7.24(2H, d, J=8.5 Hz), 7.65-7.74(1H, m), 8.15(1H,d, J=2.6 Hz)

[1064] Example 217

[1065] E0217 was prepared from E0294 and acetoxyacetic acid in a similarmanner to that of E0215. oil Mass (ESI+) : 463(M+H)+

[1066] 200MHz 1HNMR (DMSO-d6, d) : 2.07(3H, s), 2.69-2.77(2H, m),3.24-3.33(2H, m), 3.88(3H, s), 4.40(2H, s), 6.92(1H, d, J=8.7 Hz),7.18(1H, s), 7.24(4H, s), 7.75(1H, dd, J=2.7,8.7 Hz), 8.10(1H, t, J=5.6Hz), 8.19(1H, d, J=2.7 Hz)

[1067] Example 218

[1068] E0218 was prepared from E0294 and N-tert-butoxycarbonyl glycinein a similar manner to that of E0215 using N-methylmorpholine 55.8mginstead of triehtylamine. amorphous powder

[1069] IR (neat) : 3315, 1707, 1693, 1684, 1676, 1658, 1649, 1624, 1614,1564, 1547, 1533, 1510, 1500 cm−1

[1070] Mass (ESI+) : 520 (M+H)+

[1071] 200MHz 1HNMR (DMSO-d6, d) : 1.37(9H, s), 2.67-2.75(2H, m),3.22-3.33(2H, m), 3.47(2H, d, J=6.0 Hz), 3.88(3H, s), 6.80-7.00(1H,overlapping), 6.92(1H, d, J=8.8 Hz), 7.17(1H, s), 7.24(4H, s), 7.75(1H,dd, J=8.8,2.7 Hz), 7.86(1H, t, J=5.6 Hz), 8.19(1H, d, J=2.7 Hz)

[1072] Example 219

[1073] E0219 was prepared in a similar manner to that of E0215. oil

[1074] IR (KBr) : 3329, 3313, 3303, 1620, 1564, 1547, 1512 cm−1

[1075] Mass (ESI+) : 380 (M+H)+

[1076] 200MHz 1H NMR (DMSO-d6, d) : 1.08-1.22(3H, m), 2.71(2H, t,J=6.9Hz), 2.97,3.29(3H, s), 3.42-3.78(4H, m), 3.78(3H, s), 4.65(1H, t,J=5.1 Hz), 6.82,6.85(1H, s), 6.98(2H, d, J=8.9 Hz), 7.12-7.27(6H, m)

[1077] Example 220

[1078] E0220 was prepared in a similar manner to that of E0215.

[1079] Example 221

[1080] E0221 was prepared in a similar manner to that of E0215. whitepowder mp. 95-101° C.

[1081] IR (KBr) : 3421, 1693, 1647, 1603, 1566, 1549, 1516cm−1

[1082] Mass (ESI+) : 396 (M+H)+

[1083] 200MHz1HNMR (DMSO-d6,d) : 1.08-1.22(3H,m), 2.97,3.29(3H, s),3.42-3.74(4H,m),3.78(3H,s), 3.95-4.00(2H,m), 4.86(1H, t, J=5.4 Hz),6.78,6.81(1H, s), 6.91(2H, d, J=8.8 Hz), 6.98(2H, d, J=8.8 Hz), 7.16(2H,d, J=8.8 Hz), 7.23(2H, d, J=8.8 Hz)

[1084] Example 222

[1085] E0222 was prepared in a similar manner to that of E0215. whitepowder

[1086] Mass (ESI+) 398 (M+H)+

[1087] 200MHz 1H NMR (DMSO-d6, d) : 3.38(3H, s), 3.65-3.74(2H, m),3.77(3H,s),3.78(3H,s), 3.95-4.01(2H,m),4.87(1H,t,J=5.4 Hz), 6.89(1H, s),6.92(2H, d, J=8.8 Hz), 6.99(2H, s, J=8.9 Hz), 7.17(2H, d, J=8.8 Hz),7.24(2H, d, J=8.9 Hz)

[1088] Example 223

[1089] E0223 was prepared in a similar manner to that of E0215. whitepowder mp. 110-111° C.

[1090] IR (KBr) : 3425, 2979, 2945, 1606, 1570, 1549cm−1

[1091] Mass (ESI+) 397 (M+H)+

[1092] 200MHz 1H NMR (DMSO-d6, d) 1.09-1.23(3H, m), 2.98,3.28(3H, s),3.42-3.73(4H, m), 3.87(3H, s), 3.96-4.02(2H, m), 4.87(1H, t, J=5.3 Hz),6.82-6.97(4H, m), 7.21(2H, d, J=8.7 Hz), 7.63-7.72(1H, m), 8.14(1H, d,J=2.6 Hz)

[1093] Example 224

[1094] E0224 was prepared in a similar manner to that of E0215. whitepowder

[1095] Mass (ESI+) : 399 (M+H)+

[1096] 200MHz 1H NMR (DMSO-d6, d) : 3.37(3H, s), 3.66-3.74(2H, m),3.77(3H,s), 3.88(3H,s),3.96-4.02(2H,m),4.87(1H,t,J=5.5 Hz),6.88-6.97(4H, m), 7.21(2H, d, J=8.7 Hz), 7.69(1H, dd, J=2.7,8.8 Hz),8.16(1H, d, J=2.7 Hz)

[1097] Example 225

[1098] E0225 was prepared in a similar manner to that of E0215. whitepowder

[1099] Mass (ESI+) : 495(M+H)+

[1100] 400MHz 1H NMR (DMSO-d6, d) 1. 12,1.18(3H, t, J=7.0 Hz), 1.37(9H,s), 2.97,3.29(3H, s), 3.24-3.28(2H, m), 3.48,3.45(2H, q, J=7.0 Hz),3.78(3H, s), 3.95(2H, t, J=5.7 Hz), 6.78,6.81(1H, s), 6.91(2H, d,J=8.8Hz), 6.98(2H,d,J=8.8Hz), 7.00(1H, overlapping), 7.16(2H, d, J=8.8Hz), 7.23(2H, d, J=8.9 Hz)

[1101] Example 226

[1102] E0226 was prepared in a similar manner to that of E0215. whitepowder

[1103] Mass (ESI+) : 497 (M+H)+

[1104] 400MHz 1H NMR (DMSO-d6, d) : 1.37(9H, s), 3.25-3.29(2H, m),3.37(3H, brs), 3.76(3H, s), 3.78(3H, s), 3.95(2H, t, J=5.7 Hz), 6.88(1H,s), 6.91(2H, d, J=8.8 Hz), 6.99(2H, d, J=8.9 Hz), 6.97-7.00(1H, br),7.17(2H, d, J=8.8 Hz), 7.24(2H, d, J=8.9 Hz)

[1105] Example 227

[1106] E0227 was prepared in a similar manner to that of E0215. whitepowder

[1107] Mass (ESI+) : 498 (M+H)+

[1108] 200MHz 1H NMR (DMSO-d6, d) 1.37(9H, s), 3.22-3.33(2H, m),3.37(3H, s), 3.77(3H, s), 3.88(3H, s), 3.93-3.99(2H, m), 6.88-7.05(5H,m), 7.22(2H, d, J=8.6 Hz), 7.69(1H, dd, J=2.7,8.8 Hz), 8.16(1H, d, J=2.7Hz)

[1109] Example 228

[1110] This compound was obtained according to a similar manner to thatof E0215 as an oil (371.9 mg, 96%).

[1111] NMR(CDCl3); 1.43(9H, s), 3.65-3.73(2H, m), 3.79-3.82(2H, m),3.82(3H, s), 4.03(2H, t, J=5.2 Hz), 6.67(1H, s), 6.79-6.89(4H, m),7.14(2H, d, J=8.7 Hz), 7.22(2H, d, J=9.0 Hz).

[1112] MS(ESI+); 557.2(M+Na).

[1113] Example 229

[1114] This compound was obtained according to a similar manner to thatof E0289 as a white powder.

[1115] NMR(DMSO-d6),3.49-3.63(4H, m), 3.79(3H, s), 4.03(2H, t, J=4.8Hz),6.92-7.08(5H,m), 7.21(2H, d, J=8.7Hz), 7.28(2H, d, J=8.9 Hz).

[1116] MS(ESI−), 433.2(M-H).

[1117] IR(KBr); 1683cm−1

[1118] Example 230

[1119] This compound was obtained according to a similar manner to thatof E0215.

[1120] IR (film): 3320.82, 1706.69, 1668.12, 1515.77, 1249.65, 1168.65,1031.73 cm−1.

[1121] Example 231

[1122] A mixture of E0215 (300mg) and 4NHCl in dioxane (5.8ml) wasstirred at room temperature for 1.0 hour. After then, the reactionmixture was evaporated under reduced pressure to give 260mg (99%) ofE0231 as an amorphous.

[1123] IR(film) : 3226.3, 1679.7, 1513.9, 1251.6, 1083.8, 1029.8, 837.0cm−1.

[1124] Example 232

[1125] E0232 was prepared in a similar manner to that of E0231. whitepowder

[1126] IR (KBr) : 3458, 3435, 3404, 3244, 3078, 3026, 1671, 1614, 1579,1566, 1554, 1500 cm−1

[1127] Mass (ESI+) : 420 (M+H)+

[1128] 200MHz1HNMR (DMSO-d6, d) : 2.71-2.79(2H, m), 3.30-3.41(2H, m),3.44-3.54(2H, m), 3.88(3H, s), 6.93(1H, d, J=8.7 Hz), 7.22(1H, s),7.22-7.33(4H, m), 7.77(1H, dd, J=2.7,8.7 Hz), 8.10(2H, br), 8.19(1H, d,J=2.7 Hz), 8.55(1H, t, J=5.4 Hz)

[1129] Example 233

[1130] E0233 was prepared in a similar manner to that of E0231. whitepowder mp. 207-209° C.

[1131] IR (KBr) :2966, 2933, 2871, 2750, 1606, 1566, 1549, 1512cm−1

[1132] Mass (ESI+) : 395 (M+H)+

[1133] 200MHz1HNMR (DMSO-d6, d) :1.08-1.22(3H, m), 2.97,3.29(3H, s),3.17-3.22(2H, m), 3.40-3.80(2H, m), 3.78(3H, s), 4.14-4.20(2H, m),6.80,6.83(1H, s), 6.94-7.01(4H, m), 7.18-7.26(4H, m), 8.13(2H, brs)

[1134] Example 234

[1135] E0234 was prepared in a similar manner to that of E0231. whitepowder mp. 129-142° C.

[1136] IR (KBr) : 3471, 3437, 2968, 2933, 1674, 1639, 1631, 1612, 1545,1512 cm−1

[1137] Mass (ESI+) : 380 (M+H)+

[1138] 200MHz 1H NMR (DMSO-d6, d) : 1.15(6H, d, J=6.9 Hz), 3.16-3.22(2H,m), 3.68(1H, m), 3.79(3H, s), 4.15-4.20(2H, m), 6.94-7.05(5H, m),7.22(2H, d, J=8.8 Hz), 7.29(2H, d, J=8.9 Hz), 8.15(2H, brs)

[1139] Example 235

[1140] E0235 was prepared and in a similar manner to that of E0231.white powder mp. 186-189° C.

[1141] IR (KBr) : 3209, 3136, 2968, 2873, 1647, 1610, 1547, 1512cm−1

[1142] Mass (ESI+) : 335 (M+H)+

[1143] 200bMHz1HNMR (DMSO-d6, d) : 3.19(2H, t, J=4.9Hz), 3.79(3H, s),4.18(2H, t, J=4.9 Hz), 6.96-7.05(4H, m), 7.21(2H, d, J=8.8 Hz), 7.29(2H,d, J=9.0 Hz), 7.32(1H, s), 8.16(2H, brs)

[1144] Example 236

[1145] E0236 was prepared in a similar manner to that of E0231. whitepowder

[1146] Mass (ESI+) : 378 (M+H)+

[1147] 200MHz 1H NMR (DMSO-d6, d) : 1.04 (4H, d, J=6.1 Hz), 3.04 (1H,m), 3.14-3.22(2H, m), 3.80(3H, s), 4.15-4.21(2H, m), 6.93-7.05(5H, m),7.23(2H, d, J=8.6 Hz), 7.31(2H, d, J=8.9 Hz), 8.15(2H, brs)

[1148] Example 237

[1149] E0237 was prepared in a similar manner to that of E0231.amorphous powder

[1150] IR (KBr) : 3433, 3425, 3404, 3043, 3028, 3022, 2962, 1658, 1612cm−1

[1151] Mass (ESI+) : 336 (M+H)+

[1152] 200MHz 1H NMR (DMSO-d6, d) : 3.15-3.24(2H, m), 3.88(3H, s),4.16-4.22(2H, m), 6.94(1H, d, J=8.8 Hz), 7.01(2H, d, J=8.7 Hz), 7.25(2H,d, J=8.7 Hz), 7.36(1H, s), 7.75(1H, dd, J=2.6,8.8 Hz), 8.10-8.30(2H,br), 8.20(1H, d, J=2.6 Hz)

[1153] Example 238

[1154] E0238 was prepared in a similar manner to that of E0231. whitepowder mp. 156-161° C.

[1155] IR (KBr) : 2970, 1676, 1647, 1612, 1550, 1500cm−1

[1156] Mass (ESI+) : 381 (M+H)+

[1157] 200MHz 1H NMR (DMSO-d6, d) : 1.16(6H, d, J=6.9 Hz), 3.15-3.24(2H,m), 3.68(1H, m), 3.88(3H, s), 4.16-4.22(2H, m), 6.91-7.06(4H, m),7.26(2H, d, J=8.7 Hz), 7.75(1H, dd, J=2.7,8.9 Hz), 8.18(1H, d, J=2.7Hz), 8.22(2H, brs)

[1158] Example 239

[1159] This compound was obtained according to a similar manner to thatof E0231.

[1160] IR (film): 3220.5, 1679.7, 1513.9, 1461.8, 1251.6, 1081.9,1029.8, 837.0, 800.3 cm−1.

[1161] Example 240

[1162] To a solution of E0267 (75.2 mg) in dichloromethane (1 ml) wasadded triethylamine (30.4 ml) and trimethylsilyl isocyanate (36.9 ml) at0° C. After stirring for 5 hours, the mixture was quenched with waterand extracted with dichloromethane. The combined organic layers werewashed with brine, dried over magnesium sulfate, and evaporated underreduced pressure to give oil, which was purified with preparative TLC (1mm, ethyl acetate) to give oil. The oil was crystallized from a mixtureof isopropyl ether, ethyl acetate, and hexane to give E0240 as a whitesolid (39.1 mg, 51.2%).

[1163] NMR(DMSO-d6); 3.27-3.32(2H, m)), 3.79(3H, s), 3.94(2H, t, J=5.6Hz), 5.52(2H, brs, NH2), 6.15(1H, t, J=5.6 Hz, NH), 6.94(2H, d, J=8.8Hz), 7.00(2H, d, J=8.9 Hz), 7.07(1H, s), 7.20(2H, d, J=8.8 Hz), 7.28(2H,d, J=8.9 Hz).

[1164] MS(ESI+); 443.2(M+Na).

[1165] IR(KBr), 1685.5, 1656.6cm−1.

[1166] Example 241

[1167] E0241 was prepared from E0194 in a similar manner to that ofE0240. white powder mp. 139-140° C.

[1168] IR (KBr) : 3458, 3342, 1691, 1647, 1604, 1572, 1529cm−1

[1169] Mass (ESI+) : 404 (M+H)+

[1170] 200MHz 1H NMR (DMSO-d6, d) : 3.28-3.36(2H, m), 3.87(3H, s),3.92-3.98(2H, m), 5.52(2H, brs), 6.15(1H, t, J=5.5 Hz), 6.88-6.98(4H,m), 7.10(1H, t, J=54.4 Hz), 7.22(2H, d, J=8.7 Hz), 7.69(1H, dd,J=2.7,8.8 Hz), 8.14(1H, d, J=2.7 Hz)

[1171] Example 242

[1172] E0242 was prepared in a similar manner to that of E0240. whitepowdermp. 108-113° C.

[1173] IR (KBr) : 3492, 3435, 3425, 3359, 3298, 1647, 1614, 1564, 1549,1512 cm−1

[1174] Mass (ESI+) : 438 (M+H)+

[1175] 200MHz1HNMR(DMSO-d6, d) : 1.08-1.22(3H,m), 2.97,3.29(3H, s),3.20-3.85(4H, m), 3.78(3H, s), 3.94(2H, t, J=5.5 Hz),5.53(2H,s),6.15(1H,t,J=5.6Hz), 6.79,6.81(1H,s), 6.92(2H, d, J=8.8 Hz),6.99(2H, d, J=8.9 Hz), 7.17 (2H, d, J=8.8 Hz), 7.23(2H, d, J=8.9 Hz)

[1176] Example 243

[1177] E0243 was prepared from E0234 in a similar manner to that ofE0240. white powder mp. 144-145° C.

[1178] IR (KBr) : 3435, 3369, 3176, 2970, 1674, 1612, 1547, 1514cm−1

[1179] Mass (ESI+) : 423 (M+H)+

[1180] 200MHz 1H NMR (DMSO-d6, d) : 1.15(6H, d, J=6.9 Hz), 3.27-3.36(2H,m), 3.68(1H, m), 3.79(3H, s), 3.90-3.97(2H, m), 5.53(2H, s), 6.15(1H, t,J=5.6 Hz), 6.92(2H, d, J=8.7 Hz), 6.98(1H, s), 7.00(2H, d, J=8.9 Hz),7.18(2H, d, J=8.7 Hz), 7.28(2H, d, J=8.9 Hz)

[1181] Example 244

[1182] E0244 was prepared from E0235 in a similar manner to that ofE0240. white powder mp. 187-190° C.

[1183] IR (KBr) : 3379, 3201, 1649, 1614, 1579, 1527, 1506cm−1

[1184] Mass (ESI+) : 378 (M+H)+

[1185] 200MHz 1HNMR (DMSO-d6, d) : 3.27-3.34(2H, m), 3.79(3H, s),3.94(2H, t, J=5.5 Hz), 5.52(2H, brs), 6.14(1H, t, J=5.6Hz), 6.94(2H, d,J=8.8 Hz), 7.00(2H, d, J=9.0 Hz), 7.17(2H, d, J=8.8 Hz), 7.24-7.31(3H,m)

[1186] Example 245

[1187] E0245 was prepared in a similar manner to that of E0240. whitepowder mp. 136-137° C.

[1188] IR (KBr) :3433, 3342, 3221, 1658, 1612, 1581, 1549, 1512cm−1

[1189] Mass (ESI+) : 421 (M+H)+

[1190] 200MHz 1HNMR (DMSO-d6, d) : 1.04(4H, d, J=6.2 Hz), 3.03(1H, m),3.27-3.36(2H,m), 3.80(3H, s), 3.90-3.97(2H,m), 5.52(2H, s), 6.14(1H, t,J=5.6 Hz), 6.93(2H, d, J=8.8 Hz), 6.97(1H, s), 7.01(2H, d, J=8.9 Hz),7.19(2H, d, J=8.8 Hz), 7.30(2H, d, J=8.9 Hz)

[1191] Example 246

[1192] E0246 was prepared in a similar manner to that of E0240. whitepowder mp. 173-176° C.

[1193] IR (KBr) : 3473, 3334, 1630, 1624, 1601, 1583cm−1

[1194] Mass (ESI+) : 379 (M+H)+

[1195] 200MHz 1H NMR (DMSO-d6, d) : 3.27-3.36(2H, m), 3.88(3H, s),3.92-3.98(2H,m), 5.52(2H, s), 6.14(1H,t,J=5.7Hz), 6.93(1H, d, J=8.8 Hz),6.97(2H, d, J=8.8 Hz), 7.21(2H, d, J=8.8 Hz), 7.35(1H, s), 7.73(1H, dd,J=2.7,8.8 Hz), 8.20(1H, d, J=2.7 Hz)

[1196] Example 247

[1197] E0247 was prepared in a similar manner to that of E0240. whitepowder mp. 145-147° C.

[1198] IR (KBr) :3367, 3174, 2972, 1689, 1674, 1610, 1566, 1502cm−1

[1199] Mass (ESI+) : 424 (M+H)+

[1200] 200MHz 1H NMR (DMSO-d6, d) : 1.16(6H, d, J=6.9 Hz), 3.28-3.37(2H,m), 3.68(1H, m), 3.88(3H, s), 3.92-3.98(2H, m), 5.52(2H, s), 6.15(1H, t,J=5.6 Hz), 6.93(1H, d, J=8.7 Hz), 6.95(2H, d, J=8.8 Hz), 7.02(1H, s),7.22(2H, d, J=8.8 Hz), 7.73(1H, dd, J=2.7,8.7 Hz), 8.19(1H, d, J=2.7 Hz)]

[1201] Example 248

[1202] E0248 was prepared in a similar manner to that of E0240. whitepowder mp. 150.8-151.0° C.

[1203] IR (KBr) : 3496, 3361, 3294, 1705, 1674, 1647, 1603, 1581, 1568,1554, 1516 cm−1

[1204] Mass (ESI+) : 393 (M+H)+

[1205] 200MHz1HNMR (DMSO-d6, d) : 0.71-0.77(2H, m), 0.85-0.92(2H, m),1.92(1H, m), 3.27-3.37(2H, m), 3.76(3H, s), 3.92(2H, t, J=5.5 Hz),5.51(2H, s), 6.14(1H, t, J=5.5 Hz), 6.24(1H, s), 6.86-6.96(4H, m),7.07-7.15(4H, m)

[1206] Example 249

[1207] This compound was obtained according to a similar manner to thatof E0240 as an amorphous.

[1208] NMR(CDC13), 3.56-3.64(2H,m), 3.94(3H, s), 4.04(2H,t,J=4.9 Hz),4.50(2H, brs, NH2), 6.69(1H, s), 6.76(1H, d, J=8.8 Hz), 6.84(2H, d,J=8.8 Hz), 7.12(2H, d, J=8.8 Hz), 7.58(1H, dd, J=8.8, 2.8 Hz), 8.05(1H,d, J=2.8 Hz). MS(ESI+), 444.1 (M+Na)+. IR(KBr); 1650.8, 1608.3cm-1.LCMS(ESI+), 422.27(MH+).

[1209] Example 250

[1210] This compound was obtained according to a similar manner to thatof E0240 as a white powder.

[1211] NMR(CDCl3) , 3.55-3.63(2H, m) , 3.93(3H, s), 4.04 (2H, t, J=5.1Hz), 4.55(2H, brs, NH2), 5.23(1H, brt, J=5.4 Hz, NH), 6.67(1H, s),6.75(1H, t, J=55 Hz), 6.75(1H, d, J=8.4 Hz), 6.88(2H, d, J=8.8 Hz),7.13(2H, d, J=8.8 Hz), 7.56(1H, d, J=8.4, 2.9 Hz), 8.04(1H, d, J=2.9Hz).

[1212] LCMS(ESI+), 404.39(MH+).

[1213] IR(KBr) 1649cm−1

[1214] MP, 141.5 - 142.1° C.

[1215] Example 251

[1216] This compound was obtained according to a similar manner to thatof E0240 as a powder.

[1217] NMR(CDC13), 3.56-3.64(2H,m), 3.82(3H, s), 4.03(2H,t,J=5.0 Hz),4.42(2H, brs), 6.65(1H, s), 6.76(1H, t, J=55 Hz), 6.79-6.89(4H, m),7.14(2H, d, J=8.7 Hz), 7.20(2H, d, J=9.0 Hz).

[1218] MS(ESI+), 425(M+Na)+.

[1219] Example 252

[1220] To a solution of E0267 (15.3g) in ethanol (75ml) and hydrogenchloride aqueous solution (lN, 220 ml) was added dropwise a solution ofsodium cyanate (14.4 g) in water (300 ml) at 45° C. over 5 minutes.After stirring at 45° C. for 4 hours, the mixture was quenched withsaturated sodium hydrogen carbonate aqueous solution and extracted withethyl acetate. The combined organic layers were washed with brine, driedover magnesium sulfate, and evaporated to give powder. The powder wascrystallized from ethyl acetate and hexane at room temperature ˜70° C.to give E0252 as a powder (12.628 g, 81.2%).

[1221] The physical data of this compound was identical to previouslyobtained authentic sample.

[1222] Example 253

[1223] To a solution of E0267 (200 mg) in methanol (1 ml) was addedsodium methoxide methanol solution (5.2M, 0.1 ml) at room temperature.After stirring for 20 minutes, the mixture was evaporated to giveresidue. To the residue was added tetrahydrofuran, and the mixture wasfiltered and evaporated to give oil. The oil was dissolved in ethylformate (2 ml) and stirred at room temperature overnight. The mixturewas evaporated and purified with preparative TLC(1 mm, 50% ethylacetate/hexane) to give oil, which was crystallized from isopropylether, ethyl acetate, and hexane to give E0253 as a white powder (162.8mg, 83%).

[1224] NMR(CDCl3),3.68-3.76(2H,m), 3.82(3H, s), 4.06(2H,t, J=5.0 Hz),6.68(1H, s), 6.80-6.89(4H, m), 7.14(2H, d, J=8.7 Hz), 7.22(2H, d, J=9.0Hz), 8.22(1H, s).

[1225] MS(ESI+), 428.2(M+Na).

[1226] IR(KBr), 1660.4, 1614.lcm-1.

[1227] Example 254

[1228] To a solution of E0267 (800 mg) and triethylamine (0.7 ml) indichloromethane (9ml) was added dropwise acetyl chloride (0.18 ml) at 0°C. After stirring at room temperature for 1 hour, the mixture wasquenched with saturated sodium hydrogen carbonate aqueous solution andextracted with ethyl acetate (x3) . The combined organic layers werewashed with hydrogen chloride aqueous solution (1N), water, and brine,dried over magnesium sulfate, and evaporated to give oil, which waspurified with column chromatography (SiO2100 ml, eluted with 50% ethylacetate/hexane) to give oil. The oil was crystallized from a mixture ofethyl acetate and hexane at 50° C. to give E0254 as a solid (768.6 mg,94.8%).

[1229] NMR(CDCl3). 2.01(3H, s), 3.62-3.70(2H, m), 3.82(3H, s), 4.03(2H,t, J=5.0Hz) , 6.67 (iH, s) , 6.80-6.91 (4H, m) , 7.14 (2H, d, J=8.7 Hz),7.22(2H, d, J=9.0 Hz).

[1230] MP; 109.8 - 110.2° C.

[1231] IR(KBr), 1649cm−1.

[1232] MS(ESI+).442.1(M+Na).

[1233] Example 255

[1234] This compound was obtained according to a similar manner to thatof E0254 as an oil.

[1235] NMR(CDC13), 3.69(3H, s), 3.65-3.73(2H, m), 3.82(3H, s), 3.86(2H,d, J=5.9 Hz), 4.04(2H, t, J=5.1 Hz), 6.67(1H, s), 6.80-6.89(4H, m),7.14(2H, d, J=8.5 Hz), 7.22(2H, d, J-8.9 Hz),

[1236] MS(ESI+).515.2(M+Na).

[1237] IR(KBr, 20727-10), 1722.1, 1710.6, 1673.9cm−1.

[1238] Example 256

[1239] This compound was obtained according to a similar manner to thatof E0254 as an oil (82 mg, 78%).

[1240] MS(ESI+).458.2(M+Na).

[1241] IR(Neat), 1699cm−1.

[1242] NMR(CDC13); 3.54-3.62(2H, m), 3.69(3H, s), 3.82(3H, s),4.02(2H,t), 6.67(1H,s), 6.80-6.89(4H,m),7.13(2H,d,J=8.9 Hz), 7.22(2H, d,J=9.0 Hz).

[1243] Example 257

[1244] To a solution of E0275 (97.5 mg) and pyridine (0.14 ml) indichloromethane (1 ml) was added trifluoroacetic anhydride (60.6 ml) at0° C. After stirring at room temperature overnight, the mixture wasquenched with saturated sodium hydrogen carbonate aqueous solution (0.5ml), filtered with chemelute1001 (Varian), andpurified with preparativeTLC(1 mm, 50% ethyl acetate/hexane) to give E0257 as a solid (92.5 mg,76%).

[1245] MS(ESI+), 496.1(M+Na).

[1246] IR(KBr), 1705cm−1.

[1247] NMR(CDC13),3.75-3.87(2H, m), 3.82(3H, s), 4.10(4.8H, t), 6.68(1H,s), 6.83(2H, d, J=8.8 Hz), 6.88(2H, d, J=8.9 Hz), 7.16(2H, d, J=8.8 Hz),7.22(2H, d, J=8.9 Hz).

[1248] Example 258

[1249] To a solution of E0327 (400mg) in THF (5ml) was added dropwise 1NNaOH (2.5ml) at room temperature. The mixture was stirred overnight, andthen quenched with 1N HCl and CHCl3. The organic layer was separated andwater layer was extracted twice with CHCl3. The combined organic layerwas washed with water and brine, dried over Na2SO4, and evaporated underreduced pressure. The residue was washed with IPE to give 273mg (70.7%)of E0258.

[1250] IR (film) : 2971.8, 1683.6, 1629.6, 1515.8, 1315.2, 1230.4,1159.0, 1132.0, 977.7, 835.0 cm−1.

[1251] Example 259

[1252] E0259 was prepared in a similar manner to that of E0258. whitepowder

[1253] Mass (ESI+) : 355 (M+H)+

[1254] 200MHz 1HNMR (DMSO-d6, d) : 3.63-3.78(2H, m), 3.79(3H, s),3.95-4.00(2H, m), 4.86(1H, brs), 6.91(2H, d, J=8.7 Hz), 6.95(1H, s),6.99(2H, d, J=8.9 Hz), 7.16(2H, d, J=8.7 Hz), 7.24(2H, d, J=8.9 Hz),12.88(1H, brs)

[1255] Example 260

[1256] E0260 was prepared in a similar manner to that of E0258. whitepowder

[1257] Mass (ESI+) : 356 (M+H)+

[1258] 200MHz 1H NMR (DMSO-d6, d) : 3.69-3.79(2H, m), 3.88(3H, s),3.96-4.02(2H, m), 4.87(1H, br), 6.89-7.00(4H, m), 7.20(2H, d, J=8.8 Hz),7.70(1H, dd, J=2.6,8.8 Hz), 8.14(1H, d, J=2.6 Hz), 12.97(1H, br)

[1259] Example 261

[1260] E0261 was prepared from E0109 in a similar manner to that ofE0258. white powder

[1261] Mass (ESI+) : 339(M+H)+

[1262] 200MHz 1HNMR (DMSO-d6, d) : 2.70(2H, t, J=6.9 Hz), 3.59(2H, t,J=6.9 Hz), 3.79(3H, s), 4.64(1H, brs), 6.96-7.03(3H, m), 7.12-7.28(6H,m), 12.90(1H, br)

[1263] Example 262

[1264] E0262 was prepared in a similar manner to that of E0258. whitepowder

[1265] Mass (ESI+) : 454 (M+H)+

[1266] 200MHz 1H NMR (DMSO-d6, d) : 1.37(9H, s), 3.22-3.32(2H, mr),3.79(3H, s), 3.91-3.98(2H, m), 6.90(2H, d, J=8.7 Hz), 6.90-7.03(1H,overlapping), 6.95(1H, s), 6.99(2H, d, J=8.9 Hz), 7.16(2H, d, J=8.7 Hz),7.24(2H, d, J=8.9 Hz)

[1267] Example 263

[1268] E0263 was prepared in a similar manner to that of E0258.amorphous powder

[1269] Mass (ESI+) : 455 (M+H)+

[1270] 200MHz 1H NMR (DMSO-d6, d) : 1.37(9H, s), 3.22-3.32(2H, m),3.88(3H, s), 3.93-3.98(2H, m), 6.89-7.05(5H, m), 7.20(2H, d, J=8.7 Hz),7.70(1H, dd, J=2.7,8.8 Hz), 8.14(1H, d, J=2.7 Hz), 12.98(1H, br)

[1271] Example 264

[1272] E0264 was prepared from E0006 in a similar manner to that ofE0258. white powder

[1273] Mass (ESI+) : 340 (M+H)+

[1274] 200MHz 1H NMR (DMSO-d6, d) : 2.71(2H, t, J=6.9 Hz), 3.56-3.64(2H,m), 3.88(3H, s), 4.64(1H, br), 6.92(1H, d, J=8.8 Hz), 7.03(1H, s),7.16-7.28(4H, m), 7.72(1H, dd, J=8.8,2.7 Hz), 8.15(1H, d, J=2.7 Hz),12.94(1H, br)

[1275] Example 265

[1276] 4M HCl/AcOEt 0.4ml was added to a solution of E0378 (73mg) inAcOEt 1ml. The mixture was concentrated and dried in vacuo to give E026568.4mg as an amorphous powder.

[1277] IR (neat) : 3440, 2960, 1739, 1707, 1691, 1674, 1647, 1624, 1614,1566, 1549, 1533, 1500 cm−1

[1278] Mass (ESI+) : 400 (M+H)+

[1279] 200MHz1HNMR (DMSO-d6, d) : 2.73(2H, t, J=6.9Hz), 3.62(2H, t,J=6.9 Hz), 3.89(3H, s), 6.94(1H, d, J=8.8 Hz), 7.19-7.32(5H, m),7.52-7.70(3H, m), 7.80(1H, dd, J=8.8,2.7 Hz), 8.22-8.28(3H, m)

[1280] Example 266

[1281] E0266 was prepared in a similar manner to that of E0265. oil

[1282] IR (neat) : 3435, 2966, 2935, 1678, 1662, 1649, 1612, 1581, 1566,1547, 1533, 1500 cm−1

[1283] Mass (ESI+) : 366 (M+H)+

[1284] 200MHz1H NMR (DMSO-d6, d) : 1.16(6H, d, J=6.9Hz), 2.72(2H, t,J=6.9 Hz), 3.54-3.75(3H, m), 3.89(3H, s), 6.93(1H, d, J=8.8 Hz),7.05(1H, s), 7.13-7.35(4H, m), 7.76(1H, dd, J=2.7,8.8 Hz), 8.19(1H, d,J=2.7 Hz)

[1285] Example 267

[1286] To a solution of E0275 (765 mg) in ethyl acetate (1.9 ml) wasadded a solution of hydrogen chloride in ethyl acetate (4N, 0.56 ml).The mixture was evaporated to give oil, which was crystallized fromdiisopropyl ether and ethyl acetate at 65° C. to give E0267 as a solid(766.8 mg, 91.4%).

[1287] NMR(CDC13), 3.30(2H, t, J=5.0 Hz), 3.79(3H, s), 4.18(2H, t, J=5.0Hz), 6.62(1H, s), 6.83-6.88(4H, m), 7.10(2H, d, J=8.8 Hz), 7.18(2H, d,J=8.8 Hz).

[1288] NMR(DMSO-d6), 3.19(2H, brs), 3.79(3H, s), 4.18(2H, t, J=5.0 Hz),6.96-7.01(4H, m), 7.08(1H, s), 7.23-7.29(4H, m).

[1289] MS(ESI+), 378.3(MH+, free).

[1290] IR(KBr, 20727-2), 1612.2, 1513.9cm-1.

[1291] Example 268

[1292] A mixture of P0011 (30 g), chloroacetonitrile (8.52 ml),potassium iodide (4.47 g), and potassium carbonate (14.9 g) in acetone(150 ml) was stirring under reflux at 80° C. for 2.5 hours. Aftercooling to room temperature, the mixture was quenched with water (600ml) and extracted with ethyl acetate (300 ml x 2, 150 ml). The combinedorganic layers were washed with brine (300 ml), dried over magnesiumsulfate, and evaporated to give solid (36.34 g). The solid wasrecrysallized from diisopropyl ether (60 ml) and hexane (200 ml) at roomtemperature to give E0268 as a powder (31.5 g, 94%).

[1293] NMR(CDC13), 3.83(3H, s), 4.78(2H, s), 6.70(1H, s), 6.86-6.97(4H,m), 7.18-7.24(4H, m).

[1294] IR(KBr), 2051.9cm-1.

[1295] Example 269

[1296] E0269 was obtained according to a similar manner to that ofE0268. white powder

[1297] Mass (ESI+) : 346(M+H)+

[1298] 200MHz 1H NMR (DMSO-d6, d) : 0.69-0.77(2H, m), 0.86-0.96(2H, m),1.92(1H, m), 3.76(3H, s), 5.16(2H, s), 6.30(1H, s), 6.93(2H, d, J=9.0Hz), 7.02(2H, d, J=8.8 Hz), 7.10-7.21(4H, m)

[1299] Example 270

[1300] This compound was obtained according to a similar manner to thatof E0268 as a powder.

[1301] NMR(CDC13), 3.95(3H, s), 4.78(2H, s), 6.71(1H, s), 6.76(1H, t,J=55 Hz), 6.76(1H, d, J=8.4 Hz), 6.96(2H, d, J=8.9 Hz), 7.23(2H, d,J=8.9 Hz), 7.53(1H, dd, J=8.4, 2.6Hz), 8.08(1H, d, J=2.6 Hz).

[1302] MS (ESI+) 379 (M+Na)

[1303] Example 271

[1304] This compound was obtained according to a similar manner to thatof E0268.

[1305] Example 272

[1306] This compound was obtained according to a similar manner to thatof E0268.

[1307] IR (film): 1612.2, 1482.9, 1234.2, 1162.8, 1132.0, 1095.3, 973.8,835.0 cm−1.

[1308] Example 273

[1309] This compound was obtained according to a similar manner to thatof E0268.

[1310] Example 274

[1311] This compound was obtained according to a similar manner to thatof E0268. mp.96-99° C.

[1312] Mass;389 (M+1)

[1313] NMR(CDCl3,5); 1.98(1H,t,J=6.1 Hz),3.29(3H,s),3.83(3H,s),3.93-4.01(2H, m), 4.06-4.11(2H, m), 6.86(2H, d, J=8.8 Hz), 6.88(2H, d,J=9.0 Hz), 6.93(1H, s), 7.14(2H, d, J=8.8 Hz), 7.23(2H, d, J=9.0 Hz)

[1314] Example 275

[1315] To a suspension of lithium aluminum hydride (250mg) in ether (14ml) was added E0268 (1.38 g) in ether (5 ml) and tetrahydrofuran (1 ml)under ice-bath. The mixture was stirred at room temperature for 1 hour.Lithium aluminum hydride (50 mg) was added to the mixture underice-bath., and then the mixture was stirred at room temperature for 1hour. The mixture was quenched with water (0.3 ml), sodium hydroxideaqueous solution (15%, 0.3 ml), and water (0.9 ml), and then stirred atroom temperature for 30 minutes. Magnesium sulfate and celite was addedto the mixture, then the suspension was filtered and washed with ether.The filtrate was evaporated to give 1.307 g of oil. The oil purifiedwith column chromatography (SiO2, 100 ml, eluted with 20%methanol/chloroform (500 ml)) to give E0275 as an oil (1.156 g, 82.9%).

[1316] NMR(CDC13), 3.09(2H, t, J=5.1 Hz), 3.82(3H, s), 3.99(2H, t, J=5.1Hz), 6.67(1H, s), 6.82-6.89(4H, m), 7.14(2H, d, J=8.9 Hz), 7.23(2H, d,J=9.0 Hz). MS(ESI+), 378(MH+).

[1317] Example 276

[1318] To a solution of E0268 (27.43 g) in tetrahydrofuran (270 ml) wasadded borane methylsulfide complex (10M, 15 ml) at room temperature. Themixture was stirred at room temperature overnight. Then boranemethylsulfide complex (7.5 ml) was added to the mixture. After stirringat room temperature overnight, the mixture was quenched with methanol(100 ml) and evaporated under reduced pressure to give oil. The oil wasdissolved in a mixture of tetrahydrofuran (150 ml) and hydrochloric acid(6N, 100 ml), and then stirred at 40 ˜50° C. for 1 hour. To the mixturewas added dropwise aqueous sodium hydroxide solution (30%, 80 ml), andthen sodium hydrogen carbonate, and sodium chloride. The mixture wasextracted with ethyl acetate (x4). The organic layer was evaporated togive oil (31.86 g), which was purified with column chromatography (SiO2,1 L, eluted with 20% methanol/dichloromethane and concentratedammonia/methanol/chloroform (0.025:1:4)) to give oil. A solution ofhydrogen chloride in ethyl acetate (4N, 22 ml) was added to the solutionof the oil in ethyl acetate (50 ml), and the mixture was evaporated togive E0276 as an amorphous (22.87 g, 69.4%).

[1319] Example 277

[1320] E0277 was prepared in a similar manner to that of E0276. whitepowder mp. 229-231° C.

[1321] IR (KBr) : 3084, 2960, 2885, 2800, 2731, 2563, 2519, 2482, 1606,1576, 1516 cm−1

[1322] Mass (ESI+) : 350 (M+H)+

[1323] 200MHz 1HNMR (DMSO-d6, d) : 0.69-0.77 (2H, m) , 0.84-0.96(2H, m),1.93(1H,m),3.14-3.22(2H,m), 3.76(3H,s), 4.14-4.20(2H, m), 6.26(1H, s),6.94(4H, d, J=8.8 Hz), 7.14(4H, d, J=8.8 Hz), 8.21(2H, brs)

[1324] Example 278

[1325] This compound was obtained according to a similar manner to thatof E0276 without formation of hydrogen chloride salt (oil).

[1326] NMR(CDC13), 3.09(2H, t, J=5.2 Hz), 3.94(3H, s), 3.99(2H, t, J=5.2Hz), 6.77(1H, t, J=54.9 Hz), 6.67(1H, s), 6.74(2H, d, J=7.5 Hz),6.87(2H, d, J=8.9 Hz), 7.15(2H, d, J=8.7 Hz), 7.55(1H, dd, J=8.9, 2.8Hz), 8.09(1H, d, J=2.8 Hz). MS(ESI+), 361(MH+).

[1327] Example 279

[1328] This compound was obtained according to a similar manner to thatof E0276.

[1329] Example 280

[1330] This compound was obtained according to a similar manner to thatof E0276.

[1331] IR (film): 3423.0, 1612.2, 1469.5, 1240.0, 1164.8, 1132.0,1095.4, 975.8, 836.9 cm−1.

[1332] Example 281

[1333] This compound was obtained according to a similar manner to thatof E0276. mp.104-106° C.

[1334] Mass;388 (M+1)

[1335] IR(KBr);1310cm−1

[1336] NMR(CDC13,o);3.09(2H, t, J=5.1 Hz), 3.29(3H, s), 3.83(3H, s),3.99(2H, t, J=5.1 Hz), 6.83(2H, d, J=8.8 Hz), 6.88(2H, d, J=8.9 Hz),6.93(1H, s), 7.13(2H, d, J=8.8 Hz), 7.24(2H, d, J=8.9 Hz),

[1337] Example 282

[1338] Diethylazodicarboxylate 82.3mg was added to a solution of P0015(100mg), P0015-1 (152mg), and triphenylphosphine 124mg in THF 2ml. Afterstirring at ambient temperature for 5 hours, Thereaction mixture wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography eluted with AcOEt/CHC13=5% viscous oil to give E0282.

[1339] Mass (ESI+) 461 (M+H)+

[1340] 200MHz 1HNMR (DMSO-d6, d) : 1.37(9H, s), 3.22-3.33(2H, m),3.87(3H, s), 3.93-3.99(2H, m), 6.88-7.04(5H, m), 7.10(1H, t, J=54.4 Hz),7.21(2H, d, J=8.7 Hz), 7.69(1H, dd, J=2.7,8.8 Hz), 8.14(1H, d, J=2.7 Hz)

[1341] Example 283

[1342] E0283 was prepared from P0020 in a similar manner to that ofE0282. white powder

[1343] Mass (ESI+) : 482 (M+H)+

[1344] 200MHz 1HNMR (DMSO-d6, d) : 1.31(3H, t, J=7.1 Hz), 1.37(9H, s),3.22-3.32(2H,m),3.79(3H, s),3.91-3.98(2H,m), 4.32(2H, q, J=7.1 Hz),6.90(2H, d, J=8.7 Hz),6.95-7.06(1H, overlapping), 6.99(2H, d, J=8.9 Hz),7.01(1H, s), 7.17(2H, d, J=8.7 Hz), 7.25(2H, d, J=8.9 Hz)

[1345] Example 284

[1346] E0284 was prepared in a similar manner to that of E0282. whitepowder

[1347] Mass (ESI+) : 483 (M+H)+

[1348] 200MHz 1HNMR (DMSO-d6, d) : 1.31(3H, t, J=7.1 Hz), 1.37(9H, s),3.22-3.33(2H, m), 3.88(3H, s), 3.96(2H, t, J=5.7 Hz), 4.33(2H,q,J=7.1Hz), 6.89-7.05(1H, overlapping), 6.92(1H, d, J=8.9 Hz), 6.93(2H, d,J=8.7 Hz), 7.05(1H, s), 7.21(2H, d, J=8.7 Hz), 7.72(1H, dd, J=2.7,8.9Hz), 8.15(1H, d, J=2.7 Hz)

[1349] Example 285

[1350] This compound was obtained according to a similar manner to thatof E0282 as an oil.

[1351] NMR(CDC13), 1.45(9H, s), 3.50-3.58(2H, m), 3.94(3H, s), 4.02(2H,t, J=5.1 Hz), 6.70(1H, s), 6.75(1H, d, J=8.4 Hz), 6.85(2H, d, J=8.9 Hz),7.15(2H, d, J=8.9 Hz), 7.56(1H, dd, J=8.4, 2.9 Hz), 8.08(1H, d, J=2.9Hz).

[1352] MS(ESI+), 501.2(M+Na).

[1353] Example 286

[1354] This compound was obtained according to a similar manner to thatof E0282 as a powder.

[1355] NMR(CDC13), 2.89(1H, d, J=10.4 Hz, NH), 3.23(3H, s),3.67-3.78(1H, m), 3.81(3H, s), 3.99(1H, dd, J=9.2, 6.4 Hz), 4.22(1H, dd,J=9.2, 5.0 Hz), 6.67(1H, s), 6.81(2H, d, J=8.9 Hz), 6.86(2H,d,J=6.0Hz),7.10-7.29(13H,m), 7.49-7.54(6H, m).

[1356] MS(ESI+), 678.4(MH+).

[1357] Example 287

[1358] This compound was obtained according to a similar manner to thatof E0282 as an oil.

[1359] NMR(CDCl3), 1.28(3H, d, J=6.6 Hz), 1.45(9H, s), 3.82(3H, s),3.92(2H, d, J=4.1 Hz), 3.90-4.14(1H, m), 6.67(1H, s), 6.84(2H, d, J=8.9Hz), 6.86(2H, d, J=9.0 Hz), 7.13(2H, d, J=8.9 Hz), 7.23(2H, d, J=9.0Hz). MS(ESI+), 514.2(M+Na).

[1360] Example 288

[1361] This compound was obtained according to a similar manner to thatof E0282 as an oil.

[1362] NMR(CDC13), 1.28(3H, d, J=6.6 Hz), 1.45(9H, s), 3.82(3H, s),3.92(2H, d, J=4.1 Hz), 3.90-4.14(1H, m), 6.67(1H, s), 6.84(2H, d, J=8.9Hz), 6.86(2H, d, J=9.0 Hz), 7.13(2H, d, J=8.9 Hz), 7.23(2H, d, J=9.0Hz).

[1363] MS(ESI+), 514.2(M+Na).

[1364] Example 289

[1365] 4M HCl/AcOEt 1ml was added to a solution of E0282 (129mg) inAcOEt 1ml, and the mixture was stirred at ambient temperature for 1hour.The supernatant was removed by decantation. The residual oily solid waswashed with AcOEt 1ml by decantation. To the residue was added acetone2ml, and oily residual solid became white powder on stirring. This wasstirred at ambient temperature for 20minutes. The precipitates werecollected and washed with acetone to give E0289 (91.4mg) as a whitepowder.

[1366] IR (neat) : 2964, 1705, 1668, 1660, 1614, 1581, 1566, 1531, 1512cm−1

[1367] Mass (ESI+) : 361 (M+H)+

[1368] 200MHz 1H NMR (DMSO-d6, d) : 3.11-3.23(2H, m), 3.87(3H, s),4.12-4.28(2H, m), 6.90-7.02(4H, m), 7.11(1H, t, J=54.3Hz), 7.26(2H, d,J=8.6 Hz), 7.71(1H, dd, J=2.7,8.8 Hz), 8.14(1H, d, J=2.7 Hz), 8.24(2H,brs)

[1369] Example 290

[1370] This compound was obtained according to a similar manner to thatof E0289 as a white powder.

[1371] NMR(DMSO-d6), 3.17-3.21(2H, m), 3.95(3H, s), 4.19(2H, t, J=5.0Hz), 6.93(1H, d, J=8.8 Hz), 7.00(2H, d, J=8.8 Hz), 7.15(1H, s), 7.28(2H,d, J=8.8 Hz), 7.76(1H, dd, J=8.8, 2.6 Hz), 8.18(1H, d, J=2.6 Hz).

[1372] MS(ESI+), 379.1(MH+).

[1373] IR(KBr), 1612.2cm−1.

[1374] Example 291

[1375] This compound was obtained according to a similar manner to thatof E0289 as a white powder.

[1376] NMR(DMSO-d6), 2.60(3H, s), 3.28-3.33(2H, m), 3.79(3H, s),4.25(2H, t, J=4.7 Hz), 7.04-6.96(4H, m), 7.09(1H, s), 7.22-7.31(4H, m).

[1377] MS(ESI−), 426.2 (M+C1)+.

[1378] IR(KBr); 1610.2, 1515.8cm−1.

[1379] MP; 189 - 189.2° C.

[1380] Example 292

[1381] This compound was obtained according to a similar manner to thatof E0289 as a white amorphous.

[1382] NMR(DEMSO-d6),1.04(3H, d, J=6.0 Hz), 3.5-3.7(1H, m), 3.79(3H, s),3.98(1H, dd, J=10.1, 6.9 Hz), 4.11(1H, dd, J=10.1, 6.5Hz),6.96-7.04(4H,m),7.09(1H, s),7.22-7.31(4H, m).

[1383] MS(ESI+), 392.2(MH+).

[1384] Example 293

[1385] This compound was obtained according to a similar manner to thatof E0289 as a white amorphous.

[1386] NMR(DEMSO-d6),1.04(3H, d, J=6.0 Hz), 3.5-3.7(1H, m), 3.79(3H, s),3.98(1H, dd, J=10.1, 6.9 Hz), 4.11(1H, dd, J=10.1, 6.5Hz),6.96-7.04(4H,m),7.09(1H,s),7.22-7.31(4H, m).

[1387] MS(ESI+), 392.2(MH+). IR(Neat) 1612.2cm−1.

[1388] Example 294

[1389] This compound was obtained according to a similar manner to thatof E0289 as a white powder.

[1390] NMR(DMSO-d6); 2.84-3.20(4H, m), 3.88(3H, s), 6.93(1H, d,J=8.9Hz),7.19(1H,s),7.30-7.36(4H,m),7.86(1H,dd,J=8.9, 2.7 Hz), 8.19(1H,d, J=2.7 Hz).

[1391] MS(ESI+); 363.3(MH+).

[1392] IR(KBr); 1612.2, 1500.3cm−1.

[1393] Example 295

[1394] A mixture of P0012 (0.5 g), chloroacetonitrile (0.2 ml),potassium iodide (525mg), and potassium carbonate (437mg) inN,N-dimethylformamide (6 ml) was stirring at 75° C. for 6 hours. Aftercooling to room temperature, the mixture was quenched with water, andextracted with ethyl acetate (x3). The combined organic layers werewashed with water (x3) and brine, dried over magnesium sulfate, andevaporated to give E0295 as a solid (631.6 mg, 112%).

[1395] NMR(CDC13), 3.83(3H, s), 4.77(2H, s),.6.69(1H, s), 6.76(1H, t,J=55 Hz), 6.96-6.86(4H, m), 7.18-7.24(4H, m).

[1396] MS(ESI+), 378.1(M+Na).

[1397] Example 296

[1398] This compound was obtained according to a similar manner to thatof E0295 as an oil.

[1399] NMR(CDCl3);1.63(1H,t,J=5.2Hz),1.99-2.11(2H,m), 3.82(3H, s),3.82-3.91(2H, m), 4.12(2H, t, J=6.0 Hz), 6.67(1H, s), 6.84(2H, d, J=8.8Hz), 6.87(2H, d, J=8.9 Hz), 7.13(2H, d, J=8.8 Hz), 7.32(2H, d, J=8.9Hz).

[1400] IR(Neat); 1612, 1514cm−1.

[1401] MS(ESI+); 393.1(MH+), 415.1(M+Na).

[1402] Example 297

[1403] This compound was obtained according to a similar manner to thatof E0205 as an oil.

[1404] NMR(CDCl3);3.03(3H, s), 3.83(3H, s), 4.97(2H, s), 6.70(1H, s),6.88(2H, d, J=9.0 Hz), 7.01(2H, d, J=8.8 Hz), 7.17-7.26(4H, m).

[1405] IR(KBr); 1612.2, 1513.9 cm−1.

[1406] MS(ESI+),449.1(M+Na).

[1407] Example 298

[1408] This compound was obtained according to a similar manner to thatof E0295 as a white solid.

[1409] NMR(DMSO-d6), 3.65-3.73(2H, m), 3.79(3H, s), 3.98(2H, t, J=4.7Hz), 4.87(1H, t, J=5.4 Hz), 6.93(2H, d, J=8.7 Hz), 7.00(2H, d, J=8.9Hz), 7.07(1H, s), 7.19(2H, d, J=8.7 Hz), 7.28(2H, d, J=8.9 Hz).

[1410] MS(ESI+), 401.2(M+Na).

[1411] IR(KBr); 1610.3, 1511.9cm−1.

[1412] Example 299

[1413] This compound was obtained according to a similar manner to thatof E0295 as a white solid.

[1414] NMR(CDCl3),2.01(1H,t, J=6.1Hz),3.82(3H, s), 3.93-4.10(4H, m),6.66(1H, s), 6.76(1H, t, J=55.1 Hz), 6.85(2H, d, J=8.7 Hz), 6.87(2H, d,J=9.0 Hz), 7.15(2H, d, J=8.7 Hz), 7.21(2H, d, J=9.0 Hz).

[1415] MS(ESI+) ; 383.2(M+Na)

[1416] IR(KBr); 1610.3, 1513.9, 1454.1cm−1.

[1417] Example 300

[1418] This compound was obtained according to a similar manner to thatof E0295 as a white powder.

[1419] NMR(DMSO-d6); 3.78(3H, s), 4.43(2H, s), 6.80-7.53(12H, m, NH2),

[1420] MS(ESI+);396.3(M+Na)+.

[1421] IR(KBr); 1681.6, 1606.4cm−1.

[1422] Example 301

[1423] Alkylation of this compound was achieved bya similar manner tothat of E0295 to give salt free compound as an oil. Hydrogen chloridesalt formation was achieved successively by a similar manner to that ofE0172 to give E0301 as a white powder (498.7 mg, 49.6%).

[1424] NMR(DMSO-d6), 3.69(2H, t, J=5.0 Hz), 3.88(3H, s), 3.99(2H, t,J=5.0 Hz), 6.92(1H, d, J=8.7 Hz), 6.96(2H, d, J=8.8 Hz), 7.13(1H, s),7.23(2H, d, J=88.8 Hz), 7.53(1H, dd, J=8.7, 2.9 Hz), 8.18(1H, d, J=2.9Hz).

[1425] MS(ESI+), 402.1(M+Na)+, (Free).

[1426] IR(Neat), 1614, 1552cm−1.

[1427] Example 302

[1428] This compound was obtained according to a similar manner to thatof E0295 as a white solid.

[1429] NMR(CDCl3) ; 3.88 (3H- s) , 4.45 (2H, s) , 6.92 (1H, d, J=8.9Hz), 6.96(2H, d, J=8.8 Hz), 7.14(1H, s), 7.26(2H, d, J=8.8 Hz), 7.41(1H,brs, NH2), 7.56(1H, brs, NH2), 7.76(1H, dd, J=8.9, 2.5 Hz), 8.18(1H, d,J=2.5 Hz).

[1430] MS(ESI+); 415.1(M+Na).

[1431] IR(KBr); 1693.2, 1608.3cm−1.

[1432] Example 303

[1433] This compound was obtained according to a similar manner to thatof E0295 as an oil.

[1434] NMR(CDCl3); 3.94(3H, s), 3.94-4.14(4H, m), 6.68(1H, s), 6.74(1H,d, J=8.7 Hz), 6.86(1H, t, J=55.0 Hz), 6.88(2H, d, J=8.9 Hz), 7.16(2H,-d,J=8.9 Hz), 7.53(1H, dd, J=2.6, 8.7 Hz), 8.08(1H, d, J=2.6 Hz).

[1435] MS(ESI+); 384.2(M+Na).

[1436] IR(KBr), 1805.1, 1612.2cm−1.

[1437] Example 304

[1438] This compound was obtained according to a similar manner to thatof E0295 as a white powder.

[1439] NMR(DMSO-d6); 3.88(3H, s), 4.44(2H, s), 6.98-9.89(4H, m),7.10(1H, t, J=54.3 Hz), 7.24(2H, d, J=8.8 Hz), 7.39(1H, brs, NH2),7.54(1H, brs, NH2), 7.70(1H, dd, J=8.9, 2.8 Hz), 8.14(1H, d, J=2.8 Hz).

[1440] MS(ESI−); 373 (M-H)+. IR(KBr); 1662.3, 1610.3cm−1.

[1441] Example 305

[1442] This compound was obtained according to a similar manner to thatof E0298.

[1443] IR (film) : 3388.3, 1494.6, 1236.2, 1160.9, 1133.9, 1095.4,975.8, 833.1 cm−1.

[1444] Example 306

[1445] This compound was obtained according to a similar manner to thatof E0295.

[1446] Mass;384(M+1)

[1447] Example 307

[1448] To a suspension of lithium aluminum hydride (250mg) in ether (5ml) was added E0295 (630 mg) in tetrahydrofuran (1 ml) under ice-bath.After stirring at room temperature for 1 hour. the mixture was quenchedwith water (0.125 ml), sodium hydroxideaqueous solution (15%, 0.125ml),andwater (0.375 ml), and then stirred at room temperature for 30minutes. Magnesium sulfate and celite was added to the mixture, then thesuspension was filtered and washed with ether. The filtrate wasevaporated to give 0.5 g of oil. The oil was purified with columnchromatography (SiO2, 50 ml, eluted withmethanol/dichloromethane/concentrated ammonia water (1/10/0.05)) to giveoil (300 mg) . The oil was dissolved in ethyl acetate and added asolution of hydrogen chloride in ethyl acetate (4N, 1.6 ml). The mixturewas evaporated to give oil, which was crystallized from methanol anddiisopropyl ether to give E0307 as apowder (300mg, 42.7%). NMR(DMSO-d6),3.20(2H, t, J=4.9 Hz), 3.78(3H, s), 4.16(2H, t, J=4.9 Hz), 6.85(1H, s),6.94-7.01(4H, m), 7.08(1H, t, J=54.6 Hz), 7.20-7.26(4H, m).

[1449] MS(ESI+), 360.3(MH+, free).

[1450] IR(KBr, 20727-7), 1612, 1513.9 cm−1.

[1451] Example 308

[1452] This compound was obtained according to a similar manner to thatof E0307.

[1453] IR (film): 3401.8, 1610.3, 1511.9, 1469.5, 1240.0, 1162.9,1130.1, 975.8, 827.3 cm−1.

[1454] Example 309

[1455] A mixtureof P0011 (200mg), Chloromethylsulfonic acid sodium salt(274 mg), potassium iodide (298 mg), and potassium carbonate (248 mg) in1-methyl-2-pyrrolidinone (2 ml) was stirring at 150° C. overnight. Aftercooling to room temperature, the mixture was poured into a mixture ofaqueous hydrogen chloride solution (1 N), brine, and ethyl acetate. Theaqueous layer was separated and extracted with ethyl acetate (x3) . Thecombined organic layers were dried over magnesium sulfate, andevaporated under reduced pressure to give oil. The oil was purified withcolumn chromatography (SiO2 100 ml, eluted with 15%methanol/dichloromethane) to give E0309 as a brown amorphous (154.3 mg,60%) MS(ESI−); 427.1(M-H).

[1456] NMR(DMSO-d6), 3.79(3H, s), 4.52(2H, s), 7.00(2H, d, J=9.0 Hz),7.01(2H, d, J=8.9 Hz), 7.07(1H, s), 7.18(2H, d, J=9.0 Hz), 7.27(2H, d,J=8.9 Hz).

[1457] Example 310

[1458] To a solution of P0011 (1.0g) in DMF (10ml) under water coolingwas added portionwise NaH (60%in Oil, 144mg) and stirred for 1 hour.After then, III (787mg) was added and the reaction mixture was stirredat 50° C. for 5 hours. The mixture was quenched with water and extractedtwice with EtOAc. The organic layer was washed three times with waterand once with brine, dried over-MgSO4, filtered and evaporated underreduced pressure. The residue was column chromatographed on silica gel(50ml) to give 803mg (55%) of E0310 as a oil.

[1459] Example 311

[1460] This compound was obtained according to a similar manner to thatof E0310.

[1461] Example 312

[1462] The mixture of E0310 (800mg) and cHCl (100ul) in EtOH (10ml) wasstirred at room temperature for 3hours. After addition of aqueous sodiumbicarbonate, the mixture was evaporated, and extracted twice with EtOAc.The organic layer was washed with water and brine, dried over MgSO4,filtered and evaporated under reduced pressure. The residue (710mg) wascolumn chromatographed on silica gel (50ml) to give 570mg (93%) ofE0312.

[1463] IR (film): 3409.5, 1612.2, 1513.9, 1467.6, 1243.9, 1162.9,1130.1, 835.0, 835.0 cm−1.

[1464] Example 313

[1465] This compound was obtained according to a similar manner to thatof E0312. mp: 122.3-122.5° C.

[1466] IR (film): 3399.9, 1612.2, 1513.9, 1456.0, 1251.6, 1174.4,1083.8, 1033.7, 836.9, 800.3 cm−1.

[1467] Example 314

[1468] 60% Sodium hydride 39.7mg was added to a solution of P0011(255mg) in DMF 1.5ml. The mixture was stirred at ambient temperature for1hour. To this was added ethyl bromoacetate 153mg. The reaction mixturewas stirred at ambient temperature for 1hour, and then quenched byadding saturated ammonium chloride solution, and whole mixture wasextracted with AcOEt. The organic layer was washed with H2O, aqueoussodium chloride solution, dried over magnesium sulfate, and concentratedin vacuo. The residue was purified by silica gel column chromatographyeluted with AcOEt/n-hexane =30% to give E0314 (217 mg) as an oil.

[1469] Mass (ESI+) 421(M+H)+

[1470] 200 MHz 1HNMR (DMSO-d6, d) : 1.94 (3H, t, J=7.1 Hz), 3.79 (3H,s), 4.15 (2H, q, J=7.1 Hz), 4.79 (2H, s), 6.92 (2H, d, J=8.8 Hz), 6.99(2H, d, J=8.9 Hz), 7.09 (1H, s), 7.20(2H, d, J=8.8 Hz), 7.28 (2H, d,J=8.9 Hz)

[1471] Example 315

[1472] 1 M solution of diisobutylaluminum hydride in toluene 0.5 ml wasadded dropwise to a solution of E0314 (98 mg) in THF 3 ml at −50° C. Themixture was stirred at −50° C. for 1 hour, then at 5° C. for 1 hour.Additional 1 M solution of diisobutylaluminum hydride in toluene 0.5 mlwas added dropwise. After stirring at 5° C. for one more hour, thereaction was quenched by adding 10% aqueous potassium sodium tartaricacid salt, and the mixture was filtered through a celite pad. Thefiltrate was extracted with AcOEt. The organic layer was washed withsaturated aqueous sodium chloride solution, dried over magnesiumsulfate, and concentrated in vacuo. The residue was purified bypreparative thin layer silica gel chromatography developed byAcOEt/n-hexane =60%. The separated silica gel was extracted with 10%MeOH/CHCl3 and the solvent was evaporated in vacuo to give E0315 (54.5mg) as an oil, which became solid on standing.

[1473] IR (KBr) : 3431, 2931, 1612, 1564, 1549, 1512cm−1 Mass (ESI+) :379 (M+H)+

[1474] 400 MHz 1H NMR (DMSO-d6, d) : 3.67-3.72 (2H, m), 3.79 (3H, s),3.84-3.99 (2H, m), 4.87 (1H, t, J=5.4 Hz), 6.93 (2H, d, J=8.7 Hz), 7.00(2H, d, J=8.9 Hz), 7.10 (1H, s), 7.19 (2H, d, J=8.7 Hz), 7.27 (2H, d,J=8.9 Hz)

[1475] Example 316

[1476] 60% Sodium hydride 52 mg was added to a solution of P0020 (200mg) in DMF 2 ml under ice bath cooling. The mixture was stirred at sametemperature for 30 minutes. To this was added bromoacetic acid 90.3 mg.The reaction mixture was stirred at ambient temperature for 2 hours, andthen quenched by adding s1M HCl 3 ml. H2O 3 ml and diisopropyl ether 2ml were added and the mixture was stirred in an ice bath for 30 minutes.The precipitates were collected and washed with H2O and diisopropylether to give E0316 (231.2 mg) as a white powder Mass (ESI+) : 397(M+H)+

[1477] 200 MHz 1HNMR (DMSO-d6, d): 1.31 (3H, t, J=7.1 Hz), 3.79 (3H, s),4.32 (2H, q, J=7.1 Hz), 4.68 (2H, s), 6.88 (2H, d, J=8.8 Hz), 7.00 (2H,d, J=8.9 Hz), 7.02 (1H, s), 7.18 (2H, d, J=8.8 Hz), 7.26 (2H, d, J=8.9Hz), 13.05 (1H, brs)

[1478] Example 317

[1479] E0317 was prepared in a similar manner to that of E0316. whitepowder Mass (ESI+) : 398 (M+H)+

[1480] 200 MHz 1HNMR (DMSO-d6, d) :1.31 (3H, t, J=7.1 Hz), 3.88 (3H, s),4.33 (2H, q, J=7.1 Hz), 4.70 (2H, s), 6.92 (2H, d, J=8.8 Hz), 6.89-7.00(1H, m), 7.06 (1H, s), 7.22 (2H, d, J=8.8 Hz), 7.73 (1H,dd, J=2.8,8.8Hz), 8.15 (1H, d, J=2.8 Hz), 13.04(1H, brs)

[1481] Example 318

[1482] E0318 was obtained according to a similar manner to that ofE0316. oil

[1483] Mass (ESI+) : 365 (M+H)+

[1484] 200 MHz 1HNMR (DMSO-d6, d) :0.70-0.93 (4H, m), 1.70-2.00 (1H, m),3.76 (3H, s), 4.66 (2H, s), 6.25 (1H, s), 6.85 (2H, d, J=8.9 Hz), 6.92(2H, d, J=9.0 Hz), 7.06-7.16 (4H,m), 13.00 (1H,brs)

[1485] Example 319

[1486] To a suspension of sodium borohydride 19.1 mg in THF 2 ml wasadded boron trifluoride diethyl etherate 89.5 mg dropwise under ice bathcooling 2.5eq. The mixture was stirred at same temperature for 30minutes. E0316 (100 mg) was added in one portion and the mixture wasstirred at ambient temperature for 5 hours. 1M HCl 5 ml was added andthe mixture was stirredat ambient temperature for 30 minutes. Themixture was extracted with AcOEt. The organic layer was washed withsaturated aqueous sodium bicarbonate solution and saturated aqueoussodium chloride solution, dried over magnesium sulfate, and concentratedin vacuo. The residue was crystallized from diisopropyl ether to giveE0319 (68.9 mg) as a white powder.

[1487] Mass (ESI+) : 383 (M+H)+

[1488] 200 MHz 1H NMR (DMSO-d6, d) : 1.31 (3H, t, J=7.1 Hz), 3.65-3.73(2H, m), 3.79 (3H, s), 3.94-4.00 (2H, m), 4.32 (2H, q, J=7.1 Hz), 4.87(1H, t, J=5.5 Hz), 6.91(2H, d, J=8.8 Hz), 6.99 (2H, d, J=8.9 Hz), 7.01(1H, s), 7.17 (2H, d, J=8.8 Hz), 7.25 (2H, d, J=8.9 Hz)

[1489] Example 320

[1490] E0320 was prepared in a similar manner to that of E0319. whitepowder Mass (ESI+) : 384 (M+H)+

[1491] 200 MHz 1H NMR (DMSO-d6, d) : 1.31 (3H, t, J=7.1 Hz), 3.65-3.74(2H, m), 3.88 (3H, s), 3.96-4.02 (2H, m), 4.33 (2H, q, J=7.1 Hz), 4.87(1H, t, J=5.4 Hz), 6.89-6.96 (3H, m), 7.05 (1H, s), 7.21 (2H, d, J=8.7Hz), 7.72 (1H, dd, J=2.7,8.8 Hz), 8.14 (1H, d, J=2.7 Hz)

[1492] Example 321

[1493] E0321 was prepared in a similar manner to that of E0319. whitepowder mp. 142-144° C, IR (KBr) : 3246, 2924, 1612, 1566, 1547, 1516cm−1Mass (ESI+) : 351 (M+H)+

[1494] 200 MHz 1HNMR (DMSO-d6, d) : 0.68-0.77 (2H, m), 0.85-0.95 (2H,m), 1.92 (1H, m), 3.64-3.73 (2H, m), 3.76 (3H, s), 3.96 (2H, t, J=4.9Hz), 4.85 (1H, t, J=5.5 Hz), 6.24 (1H, s), 6.85-6.96 (4H, m), 7.05-7.17(4H, m)

[1495] Example 322

[1496] E0322 was prepared in a similar manner to that of E0319. whitepowder mp. 228-231° C.

[1497] IR (KBr) : 3082, 2958, 2885, 2802, 2733, 2480, 1606, 1572, 1512cm−1 Mass (ESI+) : 350 (M+H)+

[1498] 200 MHz 1HNMR (DMSO-d6, d) :0.69-0.77 (2H, m), 0.83-0.96 (2H, m),1.93 (1H,m), 3.14-3.22 (2H,m), 3.76 (3H, s), 4.14-4.20 (2H, m), 6.27(1H, s), 6.93 (4H, d, J=8.8 Hz), 7.14 (4H, d, J=8.8 Hz), 8.24(2H, brs)

[1499] Example 323

[1500] A solution of sodium sulfite 84.2 mg in H2O 1 ml was added to asolution of P0022 (258.1 mg) in EtOH 3 ml and stirred at 70° C. for 2hours. At which time, white precipitates were appeared and H2O 1 ml wasadded to dissolve the precipitates. The mixture-was stirred at 80° C.overnight to give a clear solution. This was stirred at 80° C. furtherfor 28 hours. The reaction mixture was acidifiedby lMHCl 0.7 ml,concentrated and dried under vacuo. The residue was dissolved in CHC13,dried over magnesium sulfate, all of unsoluble matter was filtered off,and concentrated in vacuo to give E0323 (245 mg) as an amorphous powder.

[1501] Mass (API-ES negative) 425 (M-H)+

[1502] 200 MHz1HNMR (DMSO-d6, d) :2.61-2.69 (2H, m), 2.78-2.91 (2H, m),3.79 (3H, s), 7.00 (2H, d, J=8.9Hz), 7.12 (1H, s), 7.17 (2H, d, J=8.6Hz), 7.22 (2H, d, J=8.6 Hz), 7.29 (2H, d, J=8.9 Hz)

[1503] Example 324

[1504] E0324 was prepared from P0023 in a similar manner to that ofE0323. amorphous powder Mass (API-ES negative) : 426 (M-H)+

[1505] 200 MHz 1HNMR (DMSO-d6, d): 2.61-2.69 (2H,m), 2.83-2.92 (2H, m),3.88 (3H, s), 6.92 (1H,d, J=8.8Hz), 7.17 (1H, s), 7.23 (4H, s), 7.75(1H, dd, J=8.8,2.7 Hz), 8.20 (1H, d, J=2.7 Hz)

[1506] Example 325

[1507] DMF 41 mg was added to a solution of E0319 (239 mg) in thionylchloride 0.6 ml and the mixture was stirred at 50° C. for 30 minutes.The reaction mixture was concentrated in vacuo. To the residue was addedtoluene 3 ml, and concentrated in vacuo. The residue was dissolved inTHF 10 ml and was added dropwise to a solution of 28% aqoueous ammoniumhydroxide solution 0.5 ml and tetrabutylammonium hydrogensulfate 19 mgin THF 4 ml under ice bath cooling. After stirring at ambienttemperature for 30 minutes, the reaction mixture was partitioned betweenAcOEt and aqueous sodium chloride solution. The organic layer was washedwith aqueous sodium chloride solution, dried overmagnesium sulfate. Theresidue was purified by silica gel column chromatography eluted withMeOH/CDCl3=2%, 5%. Pure fraction was collected and concentrated invacuo. The residual solidwas recrystallized from EtOH-diisopropyl etherto give E0325 (72.6 mg) as a white powder.

[1508] mp. 131-132° C.

[1509] IR (KBr) : 3354, 3184, 3126, 1707, 1693, 1676, 1647, 1564, 1549,1516 cm−1 Mass (ESI+) : 426 (M+H)+

[1510] 200 MHz 1HNMR (DMSO-d6, d): 2.95-3.04 (2H, m), 3.21-3.30 (2H, m),3.79 (3H, s), 6.87 (2H, s), 7.00 (2H, d, J=8.9Hz), 7.14 (1H, s),7.23-7.33 (6H, m)

[1511] Example 326

[1512] E0326 was prepared in a similar manner to that of E0325. whitepowder mp. 139-140° C.

[1513] IR (KBr) : 3230, 3132, 1610, 1568, 1527, 1500cm−1 Mass (ESI+) 441(M+H)+

[1514] 200 MHz 1H NMR (DMSO-d6, d) : 2.58 (3H, s), 2.90-3.00 (2H, m),3.25-3.33 (2H,m),3.88 (3H,s), 6.93 (1H,d,J=8.9Hz), 6.97 (1H, brs), 7.19(1H, s), 7.26 (2H, d, J=8.3 Hz), 7.34 (2H, d, J=8.3 Hz), 7.77 (1H, dd,J=8.9,2.8 Hz), 8.19 (1H, d, J=2.8 Hz)

[1515] Example 327

[1516] A mixture of E0327-0 (800 mg) and E0327-1, methyl(triphenylphosphoranylidene)-acetate (850 mg) in toluene (10 ml) wasstirred under reflux condition for 5 hrs. The mixture was evaporatedunder reduced pressure and column chromatographed on silica gel (50 ml,Hex:EtOAc=5:1) to give 795 mg(85.5%) of E0327.

[1517] IR (film): 1718.3, 1637.3, 1513.9, 1241.9, 1166.7, 1132.0, 977.7,837.0 cm−1

[1518] Example 328

[1519] To a suspension of E0258 (180 mg) in toluene (5 ml) was addethionylchloride (0.17 ml) at room temperature. The reaction mixture wasstirred at 100° C. for 5 hours until the mixture become clear solution.After then, the mixture was evaporated under reduced pressure. (becomesolid) THF was added, and then aqueous NH3 (37%) was added. The mixturewas stirred for 1 hour, and quenched with water, and extracted twicewith EtOAc. The combined organic layer was washed with sat.NaHCO3, waterand brine, dried over Na2SO4, filtered and evaporated under reducedpressure to give 170 mg (95%) of E0328 as a powder.

[1520] IR (KBr) : 3347.8, 1671.9, 1606.4, 1513.9, 1467.6, 1388.5,1236.2, 1164.8, 1132.0, 979.7, 837.0 cm−1.

[1521] Example 329

[1522] T a suspension of E0258 (200 mg) in toluene (4 ml) was addedthionylchloride (0.19 ml) at room temperature. The reaction mixture wasstirred at 10° C. for 5 hours until the mixture become clear solution.After then, the mixture was evaporated under reduced pressure. (becomesolid) THF was added, and then Me2NH (116 mg) was added. The mixture wasstirred for 1 hour, and quenched with water, and extracted twice withEtOAc. The combined organic layer was washed with sat.NaHCO3, water andbrine, dried over Na2SO4, filtered and evaporated under reduced pressureto give 45 mg (21%) of E0329 as a powder.

[1523] Filtrate (58 mg).

[1524] mp: 118-120° C.

[1525] IR (film): 1650.8, 1608.3, 1511.9, 1469.5, 1240.0, 1159.0, 1133.9cm−1.

[1526] Example 330

[1527] A mixture of E0328 (125 mg) and Pd/C (100 mg) in EtOH (10 m) wasstirred under H2 atmosphere for 3.0 hours. After filtration, a filtratewas evaporated under reduced pressure. The residue was dissolved in EtOHand filtered with syringe driven filter, and evaporated to give 85 mg ofE0330.

[1528] IR (KBr): 3342.0, 1670.0, 1511.9, 1240.0, 1160.9, 1130.1 cm−1.

[1529] Example 331

[1530] A mixture of E0138 (300 mg) and MeSNa (72 mg) in DMF (6 ml) washeated at 70° C. for 5 hours. After cooling, the reaction mixture waspartitioned between EtOAc and water. The aqueous layer was separated andextracted with EtOAc. The combined organic layer was washed with water(twice) and brine, dried over Na2SO4, filtered and evaporated. Theresidue was column chromatographed on silica gel to give 270 mg (quant)of E0331.

[1531] Example 332

[1532] E0332 was prepared from E0141 in a similar manner to that ofE0331.

[1533] oil

[1534] Mass (ESI+) : 408 (M+H)+

[1535] 200 MHz 1H NMR (DMSO-d6, d) 1.73-1.89 (2H, m), 2.03 (3H, s),2.40-2.52 (2H, m), 2.62-2.70 (2H, m), 3.88 (3H, s), 6.92 (1H, d, J=8.8Hz), 7.18 (1H, s), 7.24 (4H, s), 7.76 (1H, dd, J=8.8,2.7 Hz), 8.18 (1H,d, J=2.7 Hz)

[1536] Example 333

[1537] This compound was obtained according to a similar manner to thatof E0331.

[1538] Example 334

[1539] This compound was obtained according to a similar manner to thatof E0331.

[1540] Example 335

[1541] This compound was obtained according to a similar manner to thatof E0331

[1542] Example 336

[1543] This compound was obtained according to a similar manner to thatof E0331.

[1544] Example 337

[1545] A mixture of E0331 (250 mg) and mcpba (165 mg) in CH2Cl2 wasstirred under ice-cooling for 1 hour, and then mcpba (55 mg) was added.After stirring for 1 hour under ice cooling, the reaction mixture waspartitioned between CDCl3 and sat.NaHCO3. The organic layer wasseparated, washed with sat.NaHCO3, water and brine, dried over Na2S04,filtered and evaporated under reduced pressure. The residue was columnchromatographed on silica gel (Hex/EtOAc) to give 141 mg (52%) of E0337.

[1546] IR (film): 1511.9, 1303.6, 1240.0, 1130.1 cm−1.

[1547] Oxide: FR267958

[1548] NMR (CDCl3) : 2.599 (s, 3H), 2.85-3.21 (m, 4H), 3.828 (s, 3H),6.721 (s, 1H), 6.872 (d,J=9.0Hz,2H), 7.141 (s, 4H), 7.179 (d,J=9.0Hz,2H).

[1549] MS: (M+Na)+431.1 (M110092-2)

[1550] Example 338

[1551] This compound was obtained according to a similar manner to thatof E0337.

[1552] IR (film) : 1511.9, 1469.5, 1311.4, 1282.4, 1236.2, 1126.2,973.9, 823.5, 759.8 cm−1.

[1553] Example 339

[1554] This compound was obtained according to a similar manner to thatof E0337.

[1555] IR (film) : 1511.9, 1469.5, 1311.4, 1282.4, 1236.2, 1128.2,973.9, 823.5, 759.8 cm−1.

[1556] Example 340

[1557] This compound was obtained according to a similar manner to thatof E0337.

[1558] IR(film) : 1673.9, 1616.1, 1498.4, 1477.2, 1467.6, 1390.4,1307.5, 1290.1, 1240.0, 1160.9, 1132.0, 971.9, 756.0 cm−1.

[1559] NMR (CDCl3): 2.76-2.94 (m, 4H), 3.927 (s, 3H), 3.943 (s, 3H),6.728 (s, 1H), 6.752 (d, J=8.9Hz, 1H), 7.12-7.26 (m, 4H), 7.46-7.59 (m,1H), 8.04-8.10 (m, 1H).

[1560] MASS (M+Na)+445.1 (FR267958-N)

[1561] Example 341

[1562] To a solution of E0336 (450 mg) in dichloromethane (45 ml) wasadded MCPBA (306 mg) at room temperature. After stirring for 1 hour, thereaction mixture was washed with sat.NaHCO3 (twice) and water, driedover Na2SO4, filtered and evaporated under reduced pressure. The residuewas column chromatographed on silica gel (50 ml) to give 470 mg of E0341as an oil.

[1563] Example 342

[1564] E0342 was prepared in a similar manner to that of E0341.

[1565] white powder.

[1566] mp. 92-93° C.

[1567] IR (KBr) : 3080, 2952, 1612, 1566, 1547, 1529, 1500 cm−1 Mass(ESI+) : 424 (M+H)+

[1568] 200 MHz 1H NMR (DMSO-d6, d) : 1.87-2.00 (2H, m), 2.51 (3H, s),2.56-2.78 (4H,m), 3.88 (3H,s), 6.92 (1H,d,J=8.9Hz),7.19 (1H, s),7.21-7.31 (4H, m), 7.76 (1H, dd, J=2.7,8.9 Hz), 8.19 (1H, d, J=2.7 Hz)

[1569] Example 343

[1570] To a solution of E0336 (450 mg) in dichloromethane (45 ml) wasadded MCPBA (306 mg) at room temperature. After stirring for 1 hour, thereaction mixture was washed with sat.NaHCO3 (twice) and water, driedover Na2SO4, filtered and evaporated under reduced pressure. The residuewas column chromatographed on silica gel (50 ml) and recrystalized fromEtOH to give 168 mg (44%) of E0343.

[1571] Example 344

[1572] 3-Chloroperoxybenzoic acid (407 mg) was added to a solution ofE0342 (666.3 mg) in CH2Cl2 6 ml under ice bath cooling. The reactionmixture was stirred at ambient temperature for 1 hour. The mixture wasdiluted with CHCl3, washed with 1 M NaOH, 5% aqueous sodium thiosulfatesolution, and saturated aqueous sodium chloride solution, dried overmagnesium sulfate, and concentrated in vacuo. The residue wasrecrystallized from AcOEt-n-hexane to give E0344 (565.2 mg) as a whitepowder. mp. 121-122° C.

[1573] IR (KBr) : 3120, 2954, 1707, 1693, 1647, 1612, 1566, 1547, 1529,1500 cm−1 Mass (ESI+) : 440 (M+H)+

[1574] 200 MHz 1HNMR (DMSO-d6, d) :1.93-2.06 (2H,m), 2.67-2.75 (2H, m),2.96 (3H, s), 3.04-3.13 (2H, m), 3.88 (3H, s), 6.92 (1H, d, J=8.8 Hz),7.19 (lFH, s), 7.19-7.31 (4H, m), 7.76 (1H, dd, J=8.8,2.8 Hz), 8.19 (1H,d, J=2.8 Hz)

[1575] Example 345

[1576] Oxalylchloride 286 mg was added to a suspension of E0363 (0.43 g)in CH2Cl2 3 ml under ice bath cooling. DMF 1 drop was added and themixture was stirred at same temperature for 1 hour, and thenconcentrated in vacuo. To the residue, was added toluene andconcentrated in vacuo. The residue was dissolved in THF 5 ml and wasadded to a solution of aqueous ammoniumhydroxide solution 5 ml withunder ice bath cooling. The mixture was stirred at same temperature for1 hour, diluted with AcOEt, washed successively with 1 M HCl, saturatedaqueous sodium bicarbonate solution, and saturated aqueous sodiumchloride solution, dried over magnesium sulfate, and concentrated invacuo. The residue was purified by silica gel column chromatographyeluted with AcOEt/n-hexane=60%. The pure fraction was collected andconcentrated in vacuo and the residue was crystallized fromdiisopropylether to give E0345 (287.8 mg) as a white powder.

[1577] Mass (ESI+) : 381 (M+H)+

[1578] 200 MHz 1H NMR (DMSO-d6, d) : 1.97 (3H, s), 2.89 (2H, t, J=6.8Hz), 3.87 (3H, s), 4.21 (2H, t, J=6.8 Hz), 6.91 (1H, d, J=8.8 Hz), 6.98(1H, s), 7.22 (2H, d, J=8.4 Hz), 7.28 (2H, d, J=8.4 Hz), 7.38 (1H, brs),7.63-7.75 (1H, brs), 7.72 (1H, dd, J=2.7,8.8 Hz), 8.16 (1H, d, J=2.7 Hz)

[1579] Example 346

[1580] A mixture of E0109 (449.1 mg) and sodium methoxide 238 mg informamide 5 ml was heated at 70° C. for 5 hours. The mixture was allowedto cool to ambient temperature, and was partitioned between ethylacetate and H2O. The organic layer was washed with saturated aqueoussodium chloride solution, dried over magnesium sulfate, and concentratedin vacuo. The residue was purified by silica gel column chromatographyeluted with CHCl3, then MeOH/CHCl3=2%, 5% to give E0346 (235.7 mg) as awhite powder.

[1581] Mass (ESI+) : 338 (M+H)+

[1582] 400 MHz 1H NMR (DMSO-d6, d) : 2.70 (2H, t, J=6.9 Hz), 3.56-3.62(2H,m),3.79 (3H,s),4.65 (1H,t,J=5.1Hz), 6.92 (1H, s), 6.99 (2H, d, J=8.9Hz), 7.15 (2H, d, J=8.3 Hz), 7.20 (2H, d, J=8.3 Hz), 7.27 (2H, d, J=8.9Hz), 7.33 (1H, s), 7.64 (1H, S)

[1583] Example 347

[1584] E0347 was prepared in a similar manner to that of E0346. whitepowder Mass (ESI+) : 454 (M+H)+

[1585] 200 MHz 1H NMR (DMSO-d6, d) : 3.65-3.73 (2H, m), 3.78 (3H, s),3.94-4.00 (2H, m),4.86 (1H,t,J=5.5Hz), 6.88 (1H,s), 6.91 (2H, d, J=8.8Hz), 6.99 (2H, d, J=8.9 Hz), 7.16 (2H, d, J=8.8 Hz), 7.26 (2H, d, J=8.9Hz), 7.32 (1H, s), 7.63 (1H, s)

[1586] Example 348

[1587] E0348 was prepared in a similar manner to that of E0346. whitepowder Mass (ESI+) : 355 (M+H)+

[1588] 200 MHz 1HNMR (DMSO-d6, d) : 3.65-3.74 (2H, m), 3.87 (3H, s),3.96-4.05 (2H, m), 4.87 (1H, t, J=5.5 Hz), 6.88-6.97 (4H, mi), 7.20 (2H,d, J=8.7 Hz), 7.37 (1H, brs), 7.67-7.73 (1H, brs, overlapping), 7.71(1H, dd, J=2.6,8.8 Hz), 8.16 (1H, d, J=2.6 Hz)

[1589] Example 349

[1590] E0349 was prepared in a similar manner to that of E0346. whitepowder Mass (ESI+) : 453 (M+H)+

[1591] 400 MHz 1HNMR (DMSO-d6, d): 1.37 (9H, s), 3.24-3.29 (2H, m), 3.78(3H, s), 3.94 (2H, t, J=5.8 Hz), 6.88 (1H, s), 6.90 (2H, d, J=8.8 Hz),6.99 (2H, d, J=9.0 Hz), 6.97-7.00 (1H, br), 7.16 (2H, d, J=8.8 Hz), 7.25(2H, d, J=9.0Hz), 7.32 (1H, brs), 7.62 (1H, brs)

[1592] Example 350

[1593] E0350 was prepared in a similar manner to that of E0346. whitepowder Mass (ESI+) : 454 (M+H)+

[1594] 200 MHz 1H NMR (DMSO-d6, d) : 1.37 (9H, s), 3.22-3.33 (2H, m),3.88 (3H, s), 3.93-3.99 (2H, m), 6.88-7.10 (4H, m), 6.91 (1H, s), 7.20(2H, d, J=8.7 Hz), 7.36 (1H, brs), 7.68 (1H, brs), 7.71 (1H, dd,J=2.7,8.8 Hz), 8.16 (1H, d, J=2.7 Hz)

[1595] Example 351

[1596] E0351 was prepared in a similar manner to that of E0346. mp.168-169° C.

[1597] IR (KBr) : 3381, 3192, 1705, 1695, 1674, 1643, 1614, 1564, 1549,1516 cm−1

[1598] Mass (ESI+) : 392 (M+H)+

[1599] 400 MHz 1HNMR(DMSO-d6,d) :3.79 (3H,s),4.43 (2H,s),6.93 (2H, d,J=8.9 Hz), 7.00 (2H, d, J=9.0 Hz), 7.08 (1H, s), 7.21 (2H, d, J=8.9 Hz),7.28 (2H, d, J=9.0 Hz), 7.40 (1H, brs), 7.54 (IH, brs)

[1600] Example 352

[1601] A mixture of E0346 (433.5 mg) and N,N-dimethylacetamide dimethylacetal 856 mg in toluene 5 ml was heated at 100° C. for 40 minutes. Thereaction mixture was concentrated in vacuo. To the residue was addedtoluene and concentrated in vacuo. The residue was dissolved in toluene5 ml, hydroxylamine hydrochloride 893 mg and AcOH 3 ml was added and themixture was heated at 100° C. for 1 hour. The mixture was cooled toambient temperature, and partitioned between AcOEt and H2O, The organiclayer was washed with H2O, saturated aqueous sodium bicarbonatesolution, and saturated aqueous sodium chloride solution, dried overmagnesium sulfate, and concentrated in vacuo. The residue was purifiedby silica gel column chromatography eluted with AcOEt/n-hexane =40%,60%, 80%. The pure fraction was collected and concentrated in vacuo. Theresidue was crystallized from AcOEt/n-hexane to give E0352 (203 mg) as awhite powder. mp. 148-150° C.

[1602] IR (KBr) : 3431, 3425, 3406, 1614, 1547, 1510 cm−1 Mass (ESI+) :377 (M+H)+

[1603] 200 MHz 1H NMR (DMSO-d6, d) : 2.44 (3H, s), 2.72 (2H, t, J=6.9Hz), 3.55-3.65 (2H, m), 3.80 (3H, s), 4.66 (1H, t, J=5.1 Hz), 7.02 (2H,d, J=8.9 Hz), 7.20 (2H, d, J=9.0 Hz), 7.24 (2H, d, J=9.0 Hz), 7.28-7.36(3H, m)

[1604] Example 353

[1605] E0353 was prepared in a similar manner to that of E0352. oil Mass(ESI+) 435 (M+H)+

[1606] 200 MHz 1HNMR (DMSO-d6, d) :2.03 (3H, s), 2.44 (3H, s), 3.80 (3H,s), 4.17-4.22 (2H, m), 4.25-4.35 (2H, m), 6.97 (2H, d, J=8.7 Hz), 7.02(2H, d, J=9.0 Hz), 7.23 (2H, d, J=8.7 Hz), 7.27 (1H, s), 7.31 (2H, d,J=9.0 Hz)

[1607] Example 354

[1608] Acetic anhydride 124 mg was added to a solution of E0346 (102.6mg) and pyridine 241 mg in CH2Cl2 1 ml. The reaction mixture was stirredat ambient temperature for 1 hour. Acetic anhydride 62 mg and pyridine 1ml was added and stirred at ambient overnight. Acetic anhydride 62 mgwas added and stirred at ambient for 4 hours. The mixture wasconcentrated in vacuo, and the residue was partitioned between ethylacetate and 1 M HCl. The organic layer was washed with saturated aqueoussodium bicarbonate solution and saturated aqueous sodium chloridesolution, dried over magnesium sulfate, and concentrated in vacuo. Theresidual solid was collected and washed with diisopropyl ether to giveE0354 (76.3 mg) as a white powder.

[1609] Mass (ESI+) : 380 (M+H)+

[1610] 200 MHz 1H NMR (DMSO-d6, d) : 1.96 (3H, s), 2.87 (2H, t, J=6.8Hz), 3.78 (3H, s), 4.20 (2H, t, J=6.8Hz), 6.94 (1H, s), 6.98 (2H, is d,J=8.9 Hz), 7.15-7.30 (6H, m), 7.33 (1H, s), 7.64 (1H, s)

[1611] Example 355

[1612] E0355 was prepared in a similar manner to that of E0354.

[1613] white powder

[1614] Mass (ESI+) : 397 (M+H)+

[1615] 200 MHz 1H NMR (DMSO-d6, d) : 2.03 (3H, s), 3.87 (3H, s),4.16-4.21 (2H, m), 4.29-4.34 (2H, m), 6.88-6.98 (4H, m), 7.21 (2H, d,J=8.7 Hz), 7.37 (1H, brs), 7.68-7.70 (1H, brs,overlapping), 7.71 (1H,dd, J=2.7,8.8 Hz), 8.16 (1H, d, J=2.7 Hz)

[1616] Example 356

[1617] Phosphorus oxychloride 40.4 mg was added to DMF 0.5 ml under icebath cooling. After stirring at same temperature for 5 minutes, E0354(50 mg) was added in one portion. The reaction mixture was stirred atsame temperature for 1 hour, and quenched by adding aqueous sodiumbicarbonate solution. The mixture was extracted with ethyl acetate. Theorganic layer was washed with H2O, saturated aqueous sodium chloridesolution, dried over magnesium sulfate, and concentrated in vacuo togive E0356 (45.0 mg) as an oil.

[1618] Mass (ESI+) : 403 (M+CH3CN+H)+Mass (API-ES positive) : 362(M+H)+, 384 (M+Na)+

[1619] 200 MHz 1H NMR (DMSO-d6, d) : 1.96 (3H, s), 2.88 (2H, t, J=6.8Hz), 3.79 (3H, s), 4.20 (2H, t, J=6.8 Hz), 7.00 (2H, d, J=8.9 Hz),7.15-7.31 (6H, m), 7.36 (1H, s)

[1620] Example 357

[1621] E0357 was prepared in a similar manner to that of E0356.

[1622] oil Mass (ESI+) : 378 (M+H)+

[1623] 200 MHz 1H NMR (DMSO-d6, d) : 2.02 (3H, s), 3.79 (3H, s),4.15-4.21 (2H, m), 4.29-4.34 (2H, m), 6.93-7.04 (4H, m), 7.18 (2H, d,J=8.8 Hz), 7.24-7.31 (3H, m)

[1624] Example 358

[1625] E0358 was prepared in a similar manner to that of E0356.

[1626] oil

[1627] Mass (ESI+) : 379 (M+H)+

[1628] 200 MHz 1H NMR (DMSO-d6, d) : 2.02 (3H, s), 3.88 (3H, s),4.17-4.21 (2H, m), 4.29-4.34 (2H, m), 6.90-7.03 (3H, m), 7.22 (2H, d,J=8.8 Hz), 7.36 (1H, s), 7.74 (1H, dd, J=2.7,8.9 Hz), 8.20 (1H, d, J=2.7Hz)

[1629] Example 359

[1630] E0359 was prepared in a similar manner to that of E0356.

[1631] amorphous powder

[1632] Mass (ESI+) : 435 (M+H)+

[1633] 200 MHz 1H NMR (DMSO-d6, d) :1.37 (9H, s), 3.22-3.32 (2H, m),3.79 (3H, s), 3.92-3.98 (2H, m), 6.90-7.08 (1H, br,overlapping), 6.92(2H, d, J=8.8 Hz), 7.00 (2H, d, J=9.0 Hz), 7.16 (2H, d, J=8.8 Hz), 7.28(2H, d, J=9.0 Hz), 7.30 (1H, s)

[1634] Example 360

[1635] E0360 was prepared in a similar manner to that of E0356.

[1636] white powder

[1637] Mass (ESI+) : 436 (M+H)+

[1638] 200 MHz 1H NMR (DMSO-d6, d) : 1.37 (9H, s), 3.22-3.32 (2H, m),3.88 (3H, s), 3.93-3.99 (2H, m), 6.90-7.01 (1H, overlapping), 6.92 (1H,d, J=8.8 Hz), 6.95 (2H, d, J=8.8 Hz), 7.21 (2H, d, J=8.8 Hz), 7.34 (1H,s), 7.73 (1H, d, J=2.7,8.8 Hz), 8.20 (1H, d, J=2.7 Hz)

[1639] Example 361

[1640] E0361 was prepared from E0345 in a similar manner to that ofE0356.

[1641] oil

[1642] Mass (ESI+) : 363 (M+H)+

[1643] 200 MHz 1H NMR (DMSO-d6, d) 1.96 (3H, s), 2.89 (2H, t, J=6.8 Hz),3.88 (3H, s), 4.21 (2H, t, J=6.8 Hz), 6.92 (1H, d, J=8.8 Hz), 7.22 (2H,d, J=8.3 Hz), 7.30 (2H, d, J=8.3 Hz), 7.41 (1H, s), 7.75 (1H, dd,J=8.8,2.7 Hz), 8.20 (1H, d, J=2.7 Hz)

[1644] Example 362

[1645] A solution of acetyl chloride 0.28 ml in was added to a solutionof E0261 (441.6 mg) in CH2Cl2 4 ml and pyridine 2 ml under ice bathcooling. The reaction mixture was stirred at ambient temperature for 1hour. Acetyl chloride 0.14 ml was added and stirred-at ambienttemperature for 1 hour. The reaction was quenched by adding aqueoussodium bicarbonate solution and the mixture was stirred at ambienttemperature overnight. The mixture was acidified to pH 2 by 6M HCl andextracted with ethyl acetate. The organic layer was washed with H20 andsaturated aqueous sodium chloride solution, dried over magnesiumsulfate, and concentrated in vacuo. The residue was crystallized fromdiisopropyl ether to give E0362 (405.3 mg) as a white powder.

[1646] Mass (ESI+) : 381 (M+H)+

[1647] 200 MHz 1H NMR (DMSO-d6, d) : 1.96 (3H, s), 2.87 (2H, t, J=6.8Hz), 3.79 (3H, s), 4.20 (2H, t, J=6.8 Hz), 6.96-7.02 (3H, m), 7.15-7.27(6H, m), 12.91 (1H, br)

[1648] Example 363

[1649] E0363 was prepared in a similar manner to that of E0362.

[1650] oil

[1651] Mass (ESI+) : 382 (M+H)+

[1652] 200 MHz 1H NMR (DMSO-d6, d) : 2.04 (3H, s), 2.94 (2H, t, J=7.0Hz), 3.95 (3H, s), 4.29 (2H, t, J=7.0 Hz), 6.76 (1H, d, J=8.8 Hz), 7.08(1H, s), 7.04-7.35 (4H, m), 7.59 (1H, dd, J=2.7,8.8 Hz), 8.12 (1H, d,J=2.7 Hz)

[1653] Example 364

[1654] Oxalyl chloride 264 mg was added to a suspension of E0362 (395mg) in CH2Cl2 5 ml under ice bath cooling. DMF 1 drop was added and themixture was stirred at ambient temperature for 1 hour.

[1655] The mixture was concentrated in vacuo. To the residue was addedtoluene, and concentrated in vacuo. The residue was dissolved in CH2Cl230 ml, cooled in an ice bath, N,O-dimethylhydroxylamine hydrochloride203 mg and triethylamine 525 mg were added and the mixture was stirredat ambient temperature overnight. The mixture was diluted with AcOEt,washed successively with 1M HC1, aqueous sodium bicarbonate solution,and saturated aqueous sodium chloride solution, dried over magnesiumsulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography eluted with CHCl3, then AcOEt/CHCl3=10%, 20%to give E0364 (418.4 mg) as an oil.

[1656] Mass (ESI+) : 424 (M+H)+

[1657] 200 MHz 1H NMR (DMSO-d6, d) : 1.97 (3H, s), 2.88 (2H, t, J=6.8Hz), 3.38 (3H, s), 3.77 (3H, s), 3.78 (3H, s), 4.20 (2H, t, J=6.8 Hz),6.94-7.03 (3H, m), 7.16-7.27 (6H, m)

[1658] Example 365

[1659] E0365 was prepared from E0363 and N, O-dimethylhydroxylaminehydrochloride in a similar manner to that of E0364.

[1660] oil

[1661] Mass (ESI+) : 425 (M+H)+

[1662] 200 MHz 1H NMR (DMSO-d6, d) : 1.97 (3H, s), 2.89 (2H, t, J=6.8Hz), 3.37 (3H, s), 3.77 (3H, s), 3.88 (3H, s), 4.21 (2H, t, J=6.8 Hz),6.91 (1H, d, J=8.8 Hz), 6.98 (1H, s), 7.20-7.33 (4H, m), 7.70 (1H, dd,J=2.8,8.8 Hz), 8.15 (1H, d, J=2.8 Hz)

[1663] Example 366

[1664] To a solution of 1.0M phenylmagnesium bromide in THF 3.4 ml wasadded a solution of E0364 (106.5 mg) in THF 2 ml under ice bath cooling.After stirring at same temperature for 1 hour, the mixture was pouredinto sat.aqNH4Cl, and extracted with AcOEt. The organic layer was washedwith saturated aqueous sodium chloride solution, dried over magnesiumsulfate, and concentrated invacuo. The residue was purified by silicagel column chromatography eluted with AcOEt/n-hexane =30%, 40%, 50% togive E0366 (107 mg )as an oil. IR (neat) : 3469, 3435, 3425, 3406, 3398,3369, 2937, 1647, 1606, 1512 cm−1

[1665] Mass (ESI+) : 399 (M+H)+

[1666] 200 MHz 1H NMR (DMSO-d6, d) : 2.72 (2H, t, J=6.9 Hz), 3.56-3.66(2H,m),3.80 (3H,s),4.65 (1H,t,J=5.1Hz),7.02 (2H, d, J=8.9 Hz), 7.20 (1H,s), 7.22 (4H, s), 7.34 (2H, d, J=8.9 Hz), 7.52-7.68 (3H, m), 8.25 (2H,d, J=8.5 Hz)

[1667] Example 367

[1668] E0367 was prepared in a similar manner to that of E0366.

[1669] white powder

[1670] mp. 95-96° C.

[1671] IR (KBr) : 3498, 3476, 2966, 1678, 1649, 1612, 1547, 1512 cm−1

[1672] Mass (ESI+) 381 (M+H)+

[1673] 200 MHz 1H NMR (DMSO-d6, d) : 1.15 (6H, d, J=6.8 Hz), 3.61-3.75(3H, m), 3.79 (3H, s), 3.95-4.00 (2H, m), 4.87 (1H, t, J=5.3 Hz), 6.91(2H, d, J=8.7 Hz), 6.98 (1H, s), 7.00 (2H, d, J=8.9 Hz), 7.17 (2H, d,J=8.7 Hz), 7.28 (2H, d, J=8.9 Hz)

[1674] Example 368

[1675] E0368 was prepared in a similar manner to that of E0366.

[1676] white powder

[1677] mp.132-133 ° C.

[1678] IR (KBr) : 3390, 3334, 3288, 1707, 1670, 1612, 1564, 1549, 1512cm−1

[1679] Mass (ESI+) : 379 (M+H)+

[1680] 200 MHz 1HNMR (DMSO-d6, d) : 1.04 (4H, d, J=6.2 Hz), 3.03 (1H,m),3.65-3.73 (2H,m), 3.80 (3H, s), 3.95-4.00 (2H,m), 4.87 (1H, t, J=5.4Hz), 6.92 (2H, d, J=8.7 Hz), 6.96 (1H, s), 7.01 (2H, d, J=8.9 Hz), 7.18(2H, d, J=8.7 Hz), 7.31 (2H, d, J=8.9 Hz)

[1681] Example 369

[1682] E0369 was prepared in a similar manner to that of E0366.

[1683] white powder

[1684] mp. 108-109° C.

[1685] IR (KBr) : 3440, 2966, 1678, 1610, 1566, 1549, 1533, 1502 cm−1

[1686] Mass (ESI+) : 382 (M+H)+

[1687] 200 MHz 1H NMR (DMSO-d6, d) : 1.16 (6H, d, J=6.9 Hz), 3.64-3.74(3H, m), 3.88 (3H, s), 3.96-4.02 (2H, m), 4.87 (1H, t, J=5.4 Hz), 6.93(1H, d, J=8.9 Hz), 6.94 (2H, d, J=8.7 Hz), 7.02 (1H, s), 7.21 (2H, d,J=8.7 Hz), 7.74 (1H, dd, J=2.7,8.9 Hz), 8.18 (1H, d, J=2.7 Hz)

[1688] Example 370

[1689] E0370 was prepared in a similar manner to that of E0368.

[1690] white powder

[1691] mp. 104-106° C.

[1692] IR (KBr) : 3367, 2947, 1668, 1610, 1566, 1549, 1531 cm−1

[1693] Mass (ESI+) : 380 (M+H)+

[1694] 2500 MHz 1HNMR (DMSO-d6, d) : 1.05 (4H, d, J=6.2Hz), 3.04 (1H,m), 3.65-3.73 (2H,m), 3.89 (3H,s),3.96-4.02 (2H,m), 4.87 (1H, t, J=5.4Hz), 6.93 (1H, d, J=8.8 Hz), 6.95 (2H, d, J=8.8 Hz), 7.06 (1H, s), 7.22(2H, d, J=8.8 Hz), 7.76 (1H, dd, J=2.6,8.8 Hz), 8.21 (1H, d, J=2.6 Hz)

[1695] Example 371

[1696] E0371 was prepared in a similar manner to that of E0366.

[1697] white powder

[1698] Mass (ESI+) : 480 (M+H)+

[1699] 200 MHz 1H NMR (DMSO-d6, d) : 1.15 (6H, d, J=6.9 Hz), 1.37 (9H,s), 3.25-3.33 (2H,m),3.68 (1H,m), 3.79 (3H,s), 3.91-3.98 (2H, m), 6.90(2H, d, J=8.7 Hz), 6.90-7.05 (1H, overlapping), 6.97 (1H, s), 7.00 (2H,d, J=8.9 Hz), 7.17 (2H, d, J=8.7 Hz), 7.28 (2H, d, J=8.9 Hz)

[1700] Example 372

[1701] E0372 was prepared in a similar manner to that of E0368.

[1702] white powder

[1703] Mass (ESI+) : 477 (M+H)+

[1704] 200 MHz 1H NMR (DMSO-d6, d) : 1.04 (4H, d, J=6.2 Hz), 1.37 (9H,s), 3.04 (1H, m), 3.22-3.33 (2H, m), 3.80 (3H, s), 3.95 (2H, t,J=5.7Hz), 6.88-7.03 (1H, overlapping), 6.91 (2H, d, J=8.7 Hz), 6.97 (1H,s), 7.01 (2H, d, J=8.9 Hz), 7.18 (2H, d, J=8.7 Hz), 7.31 (2H, d, J=8.9Hz)

[1705] Example 373

[1706] E0373 was prepared in a similar manner to that of E0366.

[1707] white powder

[1708] Mass (ESI+) : 481 (M+H)+

[1709] 200 MHz 1HNMR (DMSO-d6, d) : 1.16 (6H, d, J=6.9 Hz), 1.37 (9H,s), 3.22-3.32 (2H,m), 3.68 (1H,m),3.88 (3H, s), 3.93-3.99 (2H, m),6.90-7.02 (5H, m), 7.22 (2H, d, J=8.7 Hz), 7.73 (1H, dd, J=2.7,8.8 Hz),8.18 (1H, d, J=2.7 Hz)

[1710] Example 374

[1711] E0374 was prepared in a similar manner to that of E0368.

[1712] white powder

[1713] Mass (ESI+) : 479 (M+H)+

[1714] 200 MHz 1HNMR (DMSO-d6, d) : 1.05 (4H, d, J=6.2 Hz), 1.37 (9H,s), 3.04 (1H,m), 3.23-3.33 (2H,m),3.89 (3H,s), 3.93-3.99 (2H, m),6.89-7.08 (5H, m), 7.22 (2H, d, J=8.7 Hz), 7.76 (1H, dd, J=2.7,8.8 Hz),8.21 (1H, d, J=2.7 Hz)

[1715] Example 375

[1716] E0375 was prepared from E0364 in a similar manner to that ofE0366.

[1717] oil

[1718] IR (neat) : 3487, 3469, 3435, 3408, 3398, 3369, 2966, 2933, 1678,1512 cm−1

[1719] Mass (ESI+) : 365 (M+H)+

[1720] 200 MHz1H NMR (DMSO-d6, d) : 1.19 (6H, d, J=7.9 Hz), 2.70 (2H, t,J=6.9 Hz), 3.54-3.75 (3H, m), 3.79 (3H, s), 4.64 (1H, t, J=5.1 Hz), 7.00(2H, d, J=8.9 Hz), 7.02 (1H, s), 7.16 (2H, d, J=8.6 Hz), 7.21 (2H, d,J=8.6 Hz), 7.29 (2H, d, J=8.9 Hz)

[1721] Example 376

[1722] To a solution of 1.0M methylmagnesium bromide in diethyl ether2.8 ml was added a solution of E0364 (237.6 mg) in THF 4 ml dropwiseunder ice bath cooling. After stirring at same temperature for 30 minuesthe mixture was poured into sat.aqNH4Cl, and extracted with AcOEt. Theorganic layer was washed successively with a mixture of 1M HCl andsaturated aqueous sodium chloride solution, saturated aqueous sodiumbicarbonate solution, and saturated aqueous sodium chloride solution,dried over magnesium sulfate, and concentrated in vacuo.The residue wasdissolved in THF1 ml, 1M NaOH 0.4 ml was added and the mixture wasstirred at ambient temperature for several hours. The mixture wasneutralized with 1M HCl 0.4 ml, and partitioned between AcOEt andsaturated aqueous sodium chloride solution. The organic layer was driedover magnesium sulfate, and concentrated in vacuo. The residue waspurified by silica gel column chromatography eluted withAcOEt/n-hexane=50% to give E0376 (139.1 mg) as a white powder.

[1723] Mass (ESI+) : 337 (M+H)+

[1724] 200 MHz 1H NMR (DMSO-d6, d) : 2.54 (3H, s), 2.70 (2H, t, J=6.9Hz), 3.55-3.64 (2H, m), 3.80 (3H, s), 4.65 (1H, t, J=5.1 Hz), 7.00 (2H,d, J=8.9 Hz), .7.01 (1H, s), 7.15 (2H, d, J=8.5 Hz), 7.21 (2H, d, J=8.5Hz), 7.29 (2H, d, J=8.9 Hz)

[1725] Example 377

[1726] E0377 was prepared in a similar manner to that of E0376.

[1727] oil

[1728] Mass (ESI+) : 366 (M+H)+

[1729] 200 MHz 1HNMR (DMSO-d6, d) : 1.16 (6H, d, J=6.9 Hz), 2.72 (2H, t,J=6.9 Hz), 3.55-3.75 (3H, m), 3.88 (3H, s), 4.65 (1H, t, J=5.1Hz), 6.93(1H, d, J=8.8Hz), 7.05 (1H, s), 7.17-7.29 (4H, m), 7.76 (1H, dd,J=8.8,2.7 Hz), 8.19 (1H, d, J=2.7 Hz)

[1730] Example 378

[1731] E0378 was prepared in a similar manner to that of E0376.

[1732] oil

[1733] 200 MHz 1H NMR (DMSO-d6, d) : 2.73 (2H, t, J=6.9 Hz), 3.57-3.66(2H,m),3.89 (3H,s),4.66 (1H,t,J=5.0Hz),6.94 (1H, d, J=8.8 Hz), 7.23 (1H,s), 7.15-7.35 (4H, m), 7.52-7.72 (3H, m), 7.80 (1H, dd, J=2.7,8.8 Hz),8.23-8.32 (3H, m)

[1734] Example 379

[1735] E0379 was prepared in a similar manner to that of E0376.

[1736] white powder

[1737] Mass (ESI+) : 338 (M+H)+

[1738] 200 MHz 1H NMR (DMSO-d6, d) : 2.55 (3H, s), 2.71 (2H, t, J=6.9Hz), 3.55-3.65 (2H, m), 3.89 (3H, s), 4.65 (1H, t, J=5.1 Hz), 6.93 (1H,d, J=8.8 Hz), 7.05 (1H, s), 7.19 (2H, d, J=8.6 Hz), 7.24 (2H, d,J=8.6Hz), 7.75 (1H, dd, J=2.7,8.8 Hz), 8.19 (1H, d, J=2.7 Hz)

[1739] Example 380

[1740] A mixture of E0376 (127 mg), O-methylhydroxylamine hydrochloride47.3 mg and pyridine in EtOH 3 ml was heated at 60° C. for 1 hour. Themixture was concentrated in vacuo and the residue was purified by silicagel column chromatography eluted with AcOEt/n-hexane=40%. The purefractionwas collected and concentrated invacuo. The residue wascrystallized from diisopropyl ether to give E0380 (103.2 mg) as a whitepowder.

[1741] mp. 82-86° C.

[1742] IR (KBr) : 3359, 3269, 3246, 2939, 1549, 1512cm−1

[1743] Mass (ESI+) : 366 (M+H)+

[1744] 200 MHz 1H NMR (DMSO-d6, d) : 2.20 (3H, s), 2.70 (2H, t, J=6.9Hz), 3.54-3.65 (2H, m), 3.78 (3H, s), 3.92 (3H, s), 4.65 (1H, t, J=5.0Hz), 6.77 (1H, s), 6.97 (2H, d, J=8.9 Hz), 7.12-7.26 (6H, m)

[1745] Example 381

[1746] E0381 was prepared in a similar manner to that of E0380.

[1747] white powder

[1748] mp.94-95° C.

[1749] IR (KBr) : 3469, 3433, 3423, 3404, 3400, 3371, 1647, 1549 cm−1

[1750] Mass (ESI+) : 267 (M+H)+

[1751] 200 MHz 1H NMR (DMSO-d6, d) : 2.20 (3H, s), 2.71 (2H, t, J=6.8Hz), 3.55-3.65 (2H, m), 3.87 (3H, s), 3.92 (3H, s), 4.65 (1H, t, J=5.0Hz), 6.81 (1H, s), 6.90 (1H, d, J=8.8 Hz), 7.18 (2H, d, J=8.7 Hz), 7.23(2H, d, J=8.7 Hz), 7.69 (1H, dd, J=8.8,2.7 Hz), 8.11 (1H, d, J=2.7 Hz)

[1752] Example 382

[1753] To a solution of E0314 (100 mg) in methanol (21 ml) was added asolution of methyl amine in methanol (40%, 92 ml). After stirring atroom temperature overnight, the mixture was evaporated to give oil,which was purified with preparative TLC (1 mm, 60% ethyl acetate/hexane)to give E0382 as an oil (97 mg, 100%).

[1754] NMR(CDCl3), 2.92 (3H, d, J=5.0 Hz), 3.83 (3H, s), 4.49 (2H, s),6.69 (1H, s), 6.82-6.91 (4H, m), 7.14-7.24 (4H, m).

[1755] MS(ESI+); 428.2 (M+Na).

[1756] IR(Neat, 20727-11), 1693.2 cm−1.

[1757] Example 383

[1758] Trichloroacetyl isocyanate 62.4 mg was added to a solution ofE0118 100 mg in CH2Cl2 2 ml under ice bath cooling. After stirring atambient temperature for 3 hours, the reaction mixture was concentratedinvacuo. The residue was dissolved in THF 1 ml, MeOH 1 ml, and H2O 1 ml.Potassium carbonate 153 mg was added to the reaction mixture, andstirred at ambient temperature overnight. The reaction mixture waspartitioned between AcOEt and H2O. The organic layer was washed withsaturated aqueous sodium chloride solution, dried over magnesiumsulfate, and concentrated in vacuo. The residual solid wasrecrystallized from AcOEt-n-hexane to give E0383 84.1 mg as a whitepowder.

[1759] mp. 169-170° C.

[1760] IR (KBr) : 3435, 3332, 3263, 3209, 1684, 1610, 1516 cm−1

[1761] Mass (ESI+) : 406 (M+H)+

[1762] 400 MHz 1H NMR (DMSO-d6, d) :2.84 (2H, t, J=6.8 Hz), 3.79 (3H,s), 4.10 (2H, t, J=6.8 Hz), 6.30-6.70 (2H, br), 7.00 (2H, d, J=9.0 Hz),7.14 (1H, s), 7.21 (2H, d, J=8.4 Hz), 7.26 (2H, d, J=8.4 Hz), 7.29 (2H,d, J=9.0 Hz)

[1763] Example 384

[1764] Trimethylsilyl isocyanate 42.7 mg was added to a solution ofE0158 98.2 mg and triethylamine 30 mg in CH2Cl2 1 ml under ice bathcooling. The reaction mixture was stirred at same temperature for 1 hourand concentrated in vacuo. The residue was purified by preparative thinlayer silica gel chromatography developed by MeOH/CHCl3=10%. Theseparated silica gel was extracted with 10% MeOH/CHCl3, filtered, andthe solvent was evaporated in vacuo. The residue was crystallized fromethylacetate-diisopropyl ehter to give E0384 (59.7 mg) as a whitepowder.

[1765] mp.157-158° C.

[1766] IR (KBr) : 3406, 3357, 3330, 3209, 1704, 1662, 1614, 1529, 1520cm−1

[1767] Mass (ESI+) : 405 (M+H)+

[1768] 200 MHz 1H NMR (DMSO-d6, d) N006.067: 2.62-2.70 (2H, m),3.13-3.24 (2H,m), 3.79 (3H,s),5.42 (2H, s),5.93 (1H,t,J=5.4 Hz), 7.00(2H, d, J=8.8Hz), 7.12 (1H, s), 7.21 (4H, s), 7.29 (2H, d, J=8.8 Hz)

[1769] Example 385

[1770] This compound was obtained according to a similar manner to thatof E0384.

[1771] IR (film): 3343.9, 1656.6, 1604.5, 1550.5, 1515.8, 1457.9,1342.2, 1251.6, 1029.8 cm−1.

[1772] Example 386

[1773] This compound was obtained according to a similar manner to thatof E0384.

[1774] IR (film) :3345.9, 1654.6, 1604.5, 1556.3, 1513.9, 1465.6,1240.0, 1160.9, 1132.0 cm−1.

[1775] Example 387

[1776] This compound was obtained according to a similar manner to thatof E0384.

[1777] IR (film): 3345.9, 1658.5, 1602.6, 1552.4, 1236.2, 1159.0, 1133.9cm−1.

[1778] Example 388

[1779] This compound was obtained according to a similar manner to thatof E0384.

[1780] IR(film) : 3345.9, 1658.5, 1602.6, 1552.4, 1517.7, 1236.2,1159.0, 1133.9 cm−1.

[1781] Example 389

[1782] A mixture of E0175 (150 mg) and 6 ml of 4N HCl/dioxane wasstirred at room temperature. After 2 hours, the reaction mixture wasevaporated under reduced pressure to give 128 mg (quant.) of E0389 as anoil.

[1783] IR(film): 3403.7, 1513.9, 1467.6, 1241.9, 1162.9, 1130.1 cm−1.

[1784] Example 390

[1785] This compound was obtained according to a similar manner to thatof E0389.

[1786] IR(film): 3428.8, 1662.34, 1612.2, 1500.4, 1461.8, 1390.4,1292.1, 1166.7, 1087.7, 1029.8 cm−1.

[1787] Example 391

[1788] This compound was obtained according to a similar manner to thatof E0389.

[1789] IR (film): 3403.74, 2965.98,1610.27, 1513.85, 1461.78, 1251.58,1170.58, 1085.73, 1029.80, 836.955, 800.314 cm−1.

[1790] Example 392

[1791] This compound was obtained according to a similar manner to thatof E0389.

[1792] IR (film): 3432.7, 1511.9, 1467.6, 1240.0, 1160.9, 1130.1 cm−1.

[1793] Example 393

[1794] A mixture of E0258 (10 mg) and Pd/C (100 mg) in EtOH (10 m) wasstirred under H2 atmosphere for 3.0 1 hours. After filtration, afiltrate was evaporated under reduced pressure. The resudue wasdissolved in EtOH and filtered with syringe driven filter, andevaporated to give 93 mg (93%) of E0393.

[1795] IR (film):3019.9, 1704.8, 1513.9, 1303.6, 1238.1, 1133.9 cm−1.

[1796] Example 394

[1797] T a suspension of E0258 (200 mg) in toluene (4 ml) was addedthionylchloride (0.19 ml) at room temperature. The reaction mixture wasstirred at 100° C. for 5 hours until the mixture become clear solution.After then, the mixture was evaporated under reduced pressure. (becomesolid) THF was added, and then aqueous MeNH2 (37%) was added. Themixture was stirred for 1 hour, and quenched with water, and extractedtwice with EtOAc. The combined organic layer was washed with sat.NaHCO3,water and brine, dried over Na2SO4, filtered and evaporated underreduced pressure to give 63 mg (31%) of E0394 as a powder.

[1798] mp: 155-157° C.

[1799] IR(film) 3297.7, 1662.3, 1617.9, 1513.9, 1236.2, 1162.9, 1133.9cm−1

[1800] Example 395

[1801] A suspension of E0399 (1.8 g) and potassium phtalimido (1.13 g)in N,N-dimethylformamide (6.6 ml) was stirred at 80° C. for 3 hours. Themixture was added water (700 ml) and extracted with a mixture of ethylacetate and hexane (2:1) (x4). The combined organic layers were washedwith aqueous sodium hydroxide (1N) (x2) and brine, dried over magnesiumsulfate, and evaporated to give oil, which was purified with columnchromatography (SiO2 100 ml, eluted with 30% ethyl acetate/hexane) togive oil (1.83g, 91.1%). Ethanol (15 ml) was added to the oil, then themixture was stirred at room temperature for 10 minutes. The precipitatewas filtered, washed with ethanol (3 ml), and dried under reducedpressure to give E0395 as a white solid (1.16 g, 58%).

[1802] NMR(CDCl3), 3.00 (2H, t, J=7.6 Hz), 3.93 (2H, t, J=7.6 Hz), 3.94(3H, s), 6.73 (1H,s), 6.73 (1H,d,J=8.7Hz),7.13-7.26 (4H, m), 7.49 (1H,dd, J=8.7, 2.5 Hz), 7.70-7.86 (4H, m), 8.10 (1H, d, J=2.5 Hz).

[1803] MS(ESI+), 515 (M+Na).

[1804] Example 396

[1805] 6M HCl 0.045 ml was added to a solution of E0168 (101.5 mg) inAcOEt 1 ml and EtOH 1 ml. The mixture was concentrated and dried invacuo to give E0396 (94.8 mg) as an amorphous powder.

[1806] IR (neat) : 3433, 3020, 2956, 1668, 1658, 1612, 1572, 1543, 1500cm−1

[1807] Mass (ESI+) : 377 (M+H)+

[1808] 200 MHz 1HNMR (DMSO-d6, d) : 1.76-1.92 (2H, m), 2.52-2.81 (4H,m), 3.88 (3H, s), 6.93 (1H, d, J=8.9Hz), 7.19 (1H, s), 7.26 (4H, s),7.76 (1H, dd, J=8.9,2.7 Hz), 8.19 (1H, d, J=2.7 Hz)

[1809] Example 397

[1810] To a mixture of P0002 (5.0g) and CF3COOEt (3.5 ml) in DMF (30 ml)was added NaH (1.1 g) under ice-cooling. The reaction mixture wasallowed to warm to room temperature, and stirred under 40° C. for 1hour. The reaction mixture was extracted twice with EtOAc. The organiclayer was washed with water and brine, dried over MgSO4, filtered andevaporated under reduced pressure. The residue, sodium acetate (2.23 g)and 4-methoxyphenylhydrazine (3.96 g) in acetic acid (20 ml) was stirredat room temperature for 15 hours. The mixture was extracted twice withethyl acetate. The combined organic layer was washed with water (twice),sat.NaHCO3, water and brine, dried over MgSO4, filtered and evaporatedunder reduced pressure. The residue was column chromatographed on silicagel ( Hex/EtOAc =8:1-4:1) to give 2.58 g (36%) of E0397 as an oil.

[1811] Example 398

[1812] To a solution of E0312 (326.7 mg) in ethyl acetate (3 ml) wasadded methanesulfonyl chloride (86.9 ml) and triethylamine (0.181 ml) at0° C. After stirring for 40 minutes at 0° C., the mixture was quenchedwith water and extracted with ethyl acetate (x3). The combined organiclayers were washed with water and brine, dried over sodium sulfate, andevaporated under reduced pressure to give E0398 as an oil (351.3 mg,89%).

[1813] NMR(CDC13); 3.09 (3H, s), 3.82 (3H, s), 4.22-4.26 (2H, m),4.52-4.59 (2H,m), 6.68 (1H,s), 6.75 (2H,d,J=8.7Hz), 6.87 (2H, d, J=8.9Hz), 7.16 (2H, d, J=8.7 Hz), 7.22 (2H, d, J=8.9 Hz).

[1814] Example 399

[1815] This compound was obtained according to a similar manner to thatof E0398 as a pale yellow oil (1.82 g, 98.6%). NMR(CDCl3), 2.91 (3H, s),3.07 (2H, t, J=6.8 Hz), 3.94 (3H, s), 4.43 (2H, t, J=6.8 Hz), 6.75 (1H,s), 6.78 (1H, d, J=8.2 Hz), 7.17-7.26 (4H,m), 7.58 (1H, dd, J=9.0,2.9Hz), 8.05 (1H, d, J=2.8 Hz).

[1816] MS(ESI+), 442.1 (MH+), 464.0 (M+Na).

[1817] Example 400

[1818] A suspension of E0398 (351.3 mg) and sodium thiomethoxide (162mg) in N,N-dimethylformamide (3 ml) was stirred at 60° C. for 3.5 hours.The mixture was quenched with water and extracted with ethyl acetate(x3). The combined organic layers were washed with water and brine,dried over magnesium sulfate, and evaporated to give oil. The oil waspurified with column chromatography (SiO2 50ml, elutedwith 10% ethylacetate/hexane) to give E0400 as an oil (236.7 mg, 75.3%). NMR(CDCl3);2.24 (3H, s), 2.88 (2H, t, J=6.6 Hz), 3.82 (3H, s), 4.15 (2H, t, J=6.6Hz), 6.67 (1H, s), 6.83 (2H, d, J=8.8 Hz), 6.88 (2H, d, J=9.0 Hz), 7.13(2H, d, J=8.8 Hz), 7.23 (2H, d, J=9.0 Hz).

[1819] MS(ESI+);431 (M+Na).

[1820] Example 401

[1821] To a solution of E0400 (103.5 mg) in dichloromethane (1 ml) wasadded m-chloroperbenzoic acid (134 mg) at room temperature. Afterstirring at room temperature for 1 hour, the mixture was added saturatedsodium hydrogen sulfate aqueous solution (0.5 ml) and sodium thiosulfatepentahydrate (100 mg), and stirred for 30 minutes at room temperature.The mixture was filtered by Chemelut 1001 (Varian) and evaporated togive oil, which was purified with preparative TLC (1 mm, 50% ethylacetate/hexane) to give E0401 as an amorphous (105.9 mg, 94.9%).

[1822] NMR(CDCl3; 3.07 (3H, s), 3.45 (2H, t, J=5.3 Hz), 4.44 (2H, t,J=5.3 Hz), 3.83 (3H, s), 6.69 (1H, s), 6.69-6.90 (4H, m), 7.15-7.26 (4H,m).

[1823] MS(ESI+); 463.1 (M+Na)+. IR(KBr, 20727-8), 1612.2, 1515.8 cm−1.

[1824] Example 402

[1825] To a solution of E0400 (104.8 mg) in dichloromethane (1ml) wasadded m-chloroperbenzoic acid (44.7 mg) at 0° C., and the mixture wasstirred at 0° C. for 1 hour. Then m-chloroperbenzoic acid (35 mg) wasadded to the mixture. After stirring at 0° C. for 30 minutes, themixture was quenched with saturated sodium hydrogen sulfate aqueoussolution (0.5 ml) and sodiumthiosulfate pentahydrate (100 mg), andstirred for 30 minutes at room temperature. The mixture was filtered byChemelut 1001 (Varian) and evaporated to give oil, which was purifiedwith preparative TLC (1 mm, ethyl acetate) to give 2 fractions of E0401(TLC upper) as an amorphous (40.7 mg, 37.4%) and E0402 (TLC lower) as apowder (60 mg, 55%). NMR(CDCl3; 2.70 (3H, s), 2.99-3.27 (2H, m), 3.83(3H, s), 4.40-4.46 (2H, m), 6.68 (1H, s), 6.84-6.90 (4H, m), 7.15 (2H,d, J=8.7 Hz), 7.22 (2H, d, J=9.0 Hz). MS(ESI+); 447.1 (M+Na).

[1826] IR(KBr); 1612.2, 1513.9 cm−1.

[1827] Example 403

[1828] To a solution of E0286 (500 mg) in dichloromethane (1.5 ml) wasadded successively anisol (0.5 ml) and triflutoroacetic acid (1 ml).After stirring at room temperature for 2 hours, the mixture was quenchedwith saturated sodium hydrogen carbonate aqueous solution and extractedwith ethyl acetate (x3) . The organic layers were dried over magnesiumsulfate and evaporated to give oil, which was purified with columnchromatography (SiO2 50 ml, eluted with ethyl acetate) to give E0403 asan oil (302.5 mg, 94.2%).

[1829] NMR(CDCl3, 3.77 (3H, s), 3.80 (3H, s), 3.80-3.87 (1H, m),4.21-4.28 (2H, m), 6.67 (1H, s), 6.80-6.89 (4H, m), 7.13 (2H, d, J=8.7Hz), 7.22 (2H, d, J=8.9 Hz). MS(ESI+), 436.1 (MH+).

[1830] Example 404

[1831] A solution of E0403 (104.6 mg) in methanol (3 mg) and sodiumhydroxide aqueous solution (1N, 2 mg) was stirred at room temperaturefor 3 hours. The mixture was evaporated, and methanol was added to theresidue and evaporated to give white powder, which was purified withpreparative TLC (1 mm, 20%methanol/chloroform) to give E0404 as a powder(29.9 mg, 29.5%).

[1832] NMR(DMSO-d6), 3.50-3.54 (1H,m), 3.79 (3H, s), 4.13-4.30 (2H, m),6.91-7.07 (5H, m), 7.21 (2H, d, J=8.7 Hz), 7.27 (2H, d, J=8.9 Hz).

[1833] MS(ESI−).420.4 (M-H).

[1834] IR(KBr), 1641, 1616cm−1.

[1835] Example 405

[1836] To a solution of E0403 (106.6 mg) in methanol (2 mg) was addedconcentrated ammonia solution (1 mg) . After stirring at roomtemperature overnight, the mixture was evaporated to give solid, whichwas purified with preparative TLC (1 mm, 20%methanol/chloroform) to giveE0405 as a solid (58.2 mg, 56.5%).

[1837] NMR(CDCl3, 3.75-3.82 (1H, m), 3.82 (3H, s), 4.15-4.29 (2H, m),6.67 (1H, s), 6.83-6.91 (4H, m), 7.14 (2H, d, J=6.7 Hz), 7.22 (2H, d,J=9.0 Hz).

[1838] MS(ESI+).421.4 (MH+), 462.4 (MHMeCN)+.

[1839] IR(KBr), 1658 cm−1.

[1840] Example 406

[1841] To a solution of E0403 (87.5 mg) in tetrahydrofuran (1 mg) wasadded lithium aluminum hydride (30.5 mg) at room temperature. Afterstirring at room temperature for 2 hours, the mixture was quenched withwater (30 mg), sodium hydroxide aqueous solution (15%, 30 mg), and water(90 mg), and then stirred at room temperature for 30minutes. Magnesiumsulfate and celite was added to the mixture, then the suspension wasfiltered and washed with tetrahydrofuran. The filtrate was evaporated togive oil, which was purified with preparative TLC (0.5 mm,20%methanol/chloroform) to give oil.

[1842] To a solution of the oil in ethyl acetate was added a solution ofhydrogen chloride in ethyl acetate (4N, 0.5 mg), and then the mixturewas evaporated to give E0406 as an oil (43.5 mg, 49%).

[1843] NMR(CDCl3, 3.64-4.13 (5H, m), 3.76 (3H, s), 6.60 (1H, s),6.73-6.85 (4H, m), 7.07 (2H, d, J=8.5 Hz), 7.16 (2H, d, J=8.9 Hz).

[1844] MS(ESI+), 408.1 (MH+) (Free). IR(Neat, 20727-5), 1614.1 cm−1.

[1845] Example 407

[1846] To a suspension of sodium hydride (34.8 mg) interahydrofuran (2mg) was added a solution of E0347 (208 mg) in tetrahydrofuran (1 ml) at0□, and then the mixture was stirred at room temperature for 20 minutes.Then iodomethane (54.2 ml) was added to the mixture. After stirring atroom temperature overnight, the mixture was quenched with water,extracted with ethyl acetate (x3). The combined organic layers werewashed with water (x3) and brine, dried over magnesium sulfate, andevaporated under reduced pressure to give oil, which was purified withpreparative TLC (1 mm, 30% ethyl acetate/hexane) to give E0407 as an oil(160 mg, 74.7%).

[1847] NMR(CDCl3, 1.45 (9H, s), 2.97 (3H, s), 3.59 (2H, t, J=5.5Hz),3.82 (3H, s), 4.0-4.15 (2H, m), 6.67 (1H, s), 6.80-6.91 (4H, m), 7.13(2H, d, J=8.8 Hz), 7.23 (2H, d, J=9.0 Hz).

[1848] MS(ESI+).514.2 (M+Na).

[1849] Example 408

[1850] AcCl 0.31 mg was added to a suspension of E0347 (1.29 g) andEt3NO.66 mg inCH2Cl2 10 ml under ice bath cooling. The mixture wasstirred at ambient temperature for 2 hours. AcCl 0.31 mg and Et3N 0.66mg was added and stirred at ambient temperature for 3 hours. To thismixture was added H2O and stirred at ambient temperature for a while.White precipitates were appeared, which was collected and washed withH2O and diisopropyl ether to give E0408 (879.3 mg) as a white powder.

[1851] Mass (ESI+) : 396 (M+H)+

[1852] 200 MHz 1H NMR (DMSO-d6, d) : 2.03 (3H, s), 3.78 (3H, s),4.15-4.19 (2H, m), 4.29-4.33 (2H, m), 6.89 (1H, s), 6.93 (2H, d, J=8.8Hz), 6.98 (2H, d, J=8.9 Hz), 7.17 (2H, d, J=8.8 Hz), 7.26 (2H, d, J=8.9Hz), 7.32 (1H, s), 7.63 (1H, s)

[1853] Example 409

[1854] To a solution of E0374 (61.4 mg) in CH2C12 2 mg was addedtrimethylsilyl trifluoromethanesulfonate 85.6 mg at 0° C., followed byan addition of triethylamine 39 mg. The mixture was stirred at 0° C. for30 minutes, and partitioned between AcOEt and H2O. The organic layer waswashed with saturated aqueous sodium chloride solution, dried overmagnesium sulfate, and concentrated invacuo. The residue was purified bypreparative thin layer silica gel chromatography developed by 28% NH3aq:MeOH : CHCl3=1:10:100. The separated silica gel was extracted with 28%NH3aq : MeOH : CHCl3 =1:10:100 and the solvent was evaporated in vacuo.The residu was dried under vacuo and then dissolved in EtOH 3 mg. Tothis solution was added IM HCl 0.0892 mg and concentrated in vacuo. Theresidue was dried under vacuo to give E0409 (37 mg) as an amorphouspowder.

[1855] IR (KBr) : 2958, 1668, 1662, 1612, 1581, 1568, 1549, 1531, 1500cm−1 Mass (ESI+) : 379 (M+H)+

[1856] 200 MHz 1H NMR 1.05 (4H,d,J=6.2Hz), 3.04 (1H,m),3.15-3.24 (2H,m),3.89 (3H, s), 4.16-4.22 (2H, m), 6.94 (1H, d, J=8.8 Hz), 7.00 (2H, d,J=8.7 Hz), 7.02 (1H, s), 7.27 (2H, d, J=8.7 Hz), 7.78 (1H, dd, J=2.7,8.8Hz), 8.14 (2H, brs), 8.21 (1H, d, J=2.7 Hz)

[1857] Example 410

[1858] To a solution of2-{4-[1-(4-methoxyphenyl)-3-(methylsulfonyl)-1H-pyrazol-5-yl]phenoxy}ethanamine (133 mg,0.342 mmol) in methylene chloride (5mg) was added trimethylsilyl isocyanate (118 mg, 1.03 mmol) andtriethylamine (1.39 mg, 1.37 mmol) at ambient temperature and stirredfor two days. The reaction mixture was washed with water and brine,dried over magnesium sulfate, filtered and evaporated. Purification bycolumn chromatography (silica gel, methylene chloride/methanol =20/1)followed by recrystallization from ethylacetate gave 102 mg (69%) ofE0410 as white crystals.

[1859] mp.165-167° C.

[1860] Mass;431 (M+1)

[1861] IR(KBr);1650,1310CM−1

[1862] NMR(DMSO-d6, δ); 3.32 (2H,q,J=5.5Hz), 3.33 (3H, s), 3.79 (3H, s),3.94 (2H, t, J=5.5 Hz), 5.52 (2H, s), 6.14 (1H, t, J=5.5 Hz), 6.94 (2H,d, J=8.7 Hz), 7.01 (2H, d, J=8.9 Hz), 7.11 (1H, s), 7.20 (2H, d, J=8.7Hz), 7.28 (2H, d, J=8.9 Hz),

[1863] Example 411

[1864] A solution of P0034 64 mg in DMF 1 ml was added 60% NaH 11.4 mgat 4° C. and the mixture was stirred at same temperature for 30 minutes.To the mixture was added bromoacetic acid 33 mg and the mixture wasstirred at ambient temperature for 2 hours. The reaction was quenched byadding 1 MHCl2 mg, and the mixture was extracted with AcOEt. The organiclayer was washed with H2O, sat.aqNaCl, dried over MgSO4, concentrated invacuo to give E0411 (73 mg) as crystals.

[1865] Mass (ESI+) : 355 (M+H)+200 MHz 1HNMR (DMSO-d6, d) : 3.79 (3H,s), 3.96 (3H, s), 4.63 (2H, s), 5.88 (1H, s), 6.82 (4H, d, J=9.0 Hz),7.14 (2H, d, J=9.0 Hz), 7.17 (2H, d, J=9.0 Hz)

[1866] Example 412

[1867] Boron trifluoride diethyl etherate 137 mg was added to asuspension of sodium borohydride 29.3 mg in THF 3 mg with cooling in anice bath, and the mixture was stirred at same temperature for 30minutes. To the reaction mixture was added E0411 (137 mg) in THF 3 mg inone portion and the mixture was stirred at ambient temperature for 4hours. The reacion was quenched by adding ice water containing 1M HCl 1ml, and the mixture was stirred at ambient temperature for 1 hour. Themixture was extracted with AcOEt for 2 times, the combined organiclayers were washed with sat.aqNaHCO3, sat.aqNaCl, dried over MgSO4,evaporated in vacuo. The residue was purified by preparative thin layerchromatography developed with AcOEt/n-hexane=50%. The residue wascrystallized from IPE to give E0412 (79.2 mg) as a white powder.

[1868] mp. 107-109° C.

[1869] IR (KBr) : 3334, 2935, 1693, 1612, 1564, 1520cm−1

[1870] Mass (ESI+) : 341 (M+H)+

[1871] 200 MHz 1H NMR (DMSO-d6, d) : 2.02 (1H, t, J=6.1 Hz), 3.80 (3H,s),3.91-3.99 (2H,m), 3.97 (3H, s), 4.04-4.09 (2H,m), 5.88 (1H, s), 6.82(4H, d, J=9.0 Hz), 7.14 (2H, d, J=9.0 Hz), 7.17 (2H, d, J=9.0 Hz)

[1872] Example 413

[1873] To a solution of P0034 (237 mg) in DMF 2 mg was added 60% NaH41.6 mg with cooling in an ice bath, and the mixture was stirred atambient temperature for 1 hour. To the mixture was added E0413-0 (287mg) in DMF 1 ml and the mixture was stirred at ambient temperature for13 hours, and at 60 ° C. for 3 hours. The reaction was quenched byadding sat.NH4Claq, and the mixture was extracted with AcOEt. Theorganic layer was washed with H2O, sat.aqNaCl, dried over MgSO4,concentrated in vacuo. The residue was dissolved in EtOH 4 mg, andconc.HCl 40 μL was added. After stirring at ambient temperature for 2hours, the mixture was concentrated in vacuo. The residue waspartitioned between AcOEt and sat.aqNaHCO3, and the organic layer waswashed with sat.aqNaCl, dried over MgSO4, concentrated in vacuo. Theresidue was purified by silica gel column chromatography eluted withAcOEt/n-hexane =40%, 60%. The residue was crystallized from AcOEt 1 mland IPE2 mg. The obtained crystalswere recrystallized from AcOEt 0.7 mgand IPE1.5 mg to give E0413 (196.9 mg) as white crystals. mp. 114.9-116(115) ° C. Mass (ESI+) : 341 (M+H)+200 MHz 1H NMR (DMSO-d6, d) :3.65-3.73 (2H, m), 3.75 (3H, s), 3.83 (3H,s),3.94-3.99 (2H,m),4.86(1H,t,J=5.4Hz), 6.04 (1H, s), 6.87-6.96 (4H, m), 7.10-7.16 (4H, m)

[1874] Example 414

[1875] To a solution of P0034 (100 mg) in DMF 1 ml was added 60% NaH17.5 mg with cooling in an ice bath. The mixture was stirred at ambienttemperature for 1 hour. The mixture was cooled to 0° C. To the mixturewas added 2-bromoethyl acetate 113 mg and the mixture was stirred atambient temperature for 24 hours. The reaction was quenched by addingsat.NH4Claq, and the mixture was extracted with AcOEt. The organic layerwas washed with H2O, sat.aqNaCl, dried over MgSO4, concentrated invacuo. The residue was dissolved in THF 0.9 mg and MeOH 0.9 mg. To thissolution was added 1M NaOH 0.4 mg.

[1876] The mixture was stirred at ambient temperature for 1 hour. Themixture was partitioned between AcOEt and H2O, and the aqueous layer wasreexracted with AcOEt. The combined organic layers were washed withsat.aqNaCl, dried over MgSO4, concentrated in vacuo. The residue wascrystallized from AcOEt 0.3 mg-IPE 0.9 mg to give E0414 (82.4 mg) aswhite crystals.

[1877] Mass (ESI+) : 341 (M+H)+

[1878] Preparation 35

[1879] To a solution of N′-[5- [4- (benzyloxy)phenyl]-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-N,N-dimethylurea (1.19 g) in EtOH(10 ml) and THF (10 ml) were added a solution of ammonium formate (509mg) in H2O (2 mg) and 10% Pd-C 50% wet (150 mg). The mixture wasrefluxed for 1 hour. The catalyst was filtered off through a celite padand the pad was washed with EtOH. The filtrate and combined washingswere concentrated in vacuo. To the residue were added AcOEt and H2O.White precipitates were appeared and collected and washed with H2O andIPE successively to giveN′-[5-(4-hydroxyphenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,N-dimethylurea(555 mg) as a white powder.

[1880] Mass (ESI+) : 353 (M+H)+

[1881] 200 MHz 1HNMR (DMSO-d6, d) : 2.91 (6H, s), 3.76 (3H, s), 6.57(1H, s), 6.71 (2H, d, J=8.6 Hz), 6.93 (2H, d, J=9.0 Hz), 7.01 (2H, d,J=8.6 Hz), 7.14 (2H, d, J=9.0 Hz), 8.99 (1H, s), 9.68 (1H, s)

[1882] The following compound(s) was(were) obtained in a similar mannerto that of Preparation 35.

[1883] Preparation 36

[1884]N-[5-(4-hydroxyphenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,N′,N′-trimethylurea

[1885] white powder

[1886] Mass (ESI+) : 367 (M+H)+

[1887] 200 MHz 1H NMR (DMSO-d6, d)

[1888] 2.78 (6H, s), 3.11 (3H, s), 3.76 (3H, s), 6.19 (1H, s), 6.70 (2H,d, J=8.6 Hz), 6.93 (2H, d, J=9.0 Hz), 7.03 (2H, d, J=8.6 Hz), 7.15 (2H,d, J=9.0 Hz), 9.72 (1H, s)

[1889] Preparation 37

[1890] 4-[3-ethoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol powder

[1891] Mass (ESI+) : 311 (M+H)+

[1892] 200 MHz 1HNMR (DMSO-d6, d) : 1.32 (3H, t, J=7.0 Hz), 3.75 (3H,s), 4.16 (2H, q, J=7.0 Hz), 5.96 (1H, s), 6.70 (2H, d, J=8.6 Hz), 6.91(2H, d, J=8.9 Hz), 7.01 (2H, d, J=8.6 Hz), 7.11 (2H, d, J=8.9 Hz), 9.74(1H, brs)

[1893] Preparation 38

[1894] 4-[3-isobutoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenol whitepowder

[1895] Mass (ESI+) : 339 (M+H)+

[1896] 200 MHz 1H NMR (CDCl3, d) : 1.02 (6H, d, J=6.6 Hz), 2.10 (1H, m),3.79 (3H, s), 3.98 (6.6H, d, J=2Hz), 538 (1H, s), 5.87 (1H, s), 6.72(2H, d, J=8.6 Hz), 6.81 (2H, d, J=9.0 Hz), 7.07 (2H, d, J=8.6 Hz), 7.16(2H, d, J=9.0 Hz)

[1897] Preparation 39

[1898] 4-[3-(2-methoxyethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol

[1899] white powder

[1900] Mass (ESI+) : 341 (M+H)+

[1901] 200 MHz 1H NMR (DMSO-d6, d) : 3.30 (3H, s), 3.62-3.67 (2H, m),3.75 (3H, s),4.21-4.26 (2H,m),5.98 (1H,s), 6.70 (2H,d,J=8.6 Hz), 6.91(2H, d, J=9.0 Hz), 7.01 (2H, d, J=8.6 Hz), 7.12 (2H, d, J=9.0 Hz), 9.69(1H, s)

[1902] Preparation 40

[1903] 4-[3-(2-ethoxyethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol

[1904] white powder

[1905] Mass (ESI+) : 355 (M+H)+

[1906] 200 MHz 1H NMR (DMSO-d6, d) : 1.13 (3H, t, J=7.0 Hz), 3.49 (2H,q, J=7.0 Hz), 3.65-3.71 (2H, m), 3.75 (3H, s), 4.20-4.25 (2H, m), 5.99(1H, s), 6.70 (2H, d, J=8.6 Hz), 6.91 (2H, d, J=9.0 Hz), 7.01 (2H, d,J=8.6 Hz), 7.12 (2H, d, J=9.0 Hz), 9.72 (1H, s)

[1907] Preparation 41

[1908]2-{[5-(4-hydroxyphenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]oxy}-N,N-dimethylacetamide

[1909] white powder

[1910] Mass (ESI+) : 368 (M+H)+

[1911] 200 MHz 1HNMR (DMSO-d6, d) : 2.84 (3H, s), 2.97 (3H, s), 3.75(3H, s), 4.87 (2H, s), 6.01 (1H, s), 6.70 (2H, d, J=8.6Hz), 6.92 (2H, d,J=9.0 Hz), 7.01 (2H, d, J=8.6 Hz), 7.10 (2H, d, J=9.0 Hz), 9.71 (1H, s)

[1912] Preparation 42

[1913] 4-[3-methoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenol

[1914] white powder

[1915] MS (ESI+) : m/z 298 (M+H)+

[1916] 200 MHz 1HNMR (DMSO-d6, d) : 3.84 (6H, s), 6.05 (1H, s), 6.73(2H, d, J=8.6 Hz), 6.85 (1H, d, J=8.8 Hz), 7.05 (2H, d, J=8.6 Hz), 7.59(1H, dd, J=8.8,2.7 Hz), 7.98 (1H, d, J=2.7 Hz), 9.77 (1H, s)

[1917] Preparation 43

[1918] 4-[3-ethoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenol

[1919] white powder

[1920] MS (ESI+) : m/z 312 (M+H)+

[1921] 200 MHz 1HNMR (DMSO-d6, d) : 1.33 (3H, t, J=7.0 Hz), 3.84 (3H,s), 4.18 (2H, q, J=7.0 Hz), 6.03 (1H, s), 6.73 (2H, d, J=8.6 Hz), 6.84(1H, d, J=8.7 Hz), 7.05 (2H, d, J=8.6 Hz), 7.57 (1H, dd, J=2.6,8.7 Hz),7.97 (1H, d, J=2.6 Hz), 9.76 (1H, s)

[1922] Preparation 44

[1923]4-[1-(4-methoxyphenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenol

[1924] MASS (ESI+): m/z =371.2 (M+Na).

[1925] 1HNMR ( 400 MHz, CDCl3): 2.15 ( 3H, s), 3.78 ( 3H, s), 6.79 (2H,d, J =8.9Hz ), 6.8 ( 2H, d, J =8.6Hz ), 7.01 ( 2H, d, J =8.6 Hz ), 7.13( 2H, d, J =8.9 Hz ).

[1926] Preparation 45

[1927] 4-[3-cyclopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenol

[1928] white powder

[1929] MS(ESI+) : m/z 308 (M+H)

[1930] 1HNMR ( 200 MHz, CDCl3) 0.76-0.85 ( 2H, m), 0.93 - 1.06 (2H, m),1.97-2.08 (1H, m), 3.91 (3H, s), 6.08 ( 1H, s), 6.15 (1H, s), 6.68-6.76(3H, m), 7.04 ( 2H, d, J =8.6 Hz ), 7.56 ( 1H, dd, J =2.7, 6.2 Hz), 8.02(1H, d, J =2.7 Hz

[1931] Preparation 46

[1932]4-[3-(cyclopentyloxy)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenol

[1933] white powder

[1934] MS (ESI+) :m/z 352 (M+H)

[1935] 1HNMR (200 MHz, DMSOd6): 1.09-2.41 (8H, m), 3.84 ( 3H, s), 4.92-5(1H, m), 6.01 (1H, s), 6.73 (2H, d, J=8.6 Hz), 6.84 ( 1H, d, J =8.8 Hz), 7.05 ( 2H, d, J =8.6 Hz ), 7.57 (1H, dd, J =2.7 , 8.8 Hz), 7.97 (1H,d, J =2.7 Hz ), 9.76 (1H, brs)

[1936] Preparation 47

[1937]4-[1-(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]phenol

[1938] white powder

[1939] MS (ESI+) : m/z 365 (M+H)

[1940] 1HNMR (200 MHz, DMSOd6): 3.76 (3H, s), 4.8 ( 1H, d, J =9 Hz ),4.89 ( 1H, d, J =9 Hz ), 6.15 ( 1H, s), 6.71 (2H, d, J=8.6 Hz) ), 6.93 (2H, d, J =8.9 Hz) ), 7.03 ( 2H, d, J =8.6 Hz) ), 7.14 ( 2H, d, J =8.9Hz) ), 9.74 ( 1H, brs)

[1941] Preparation 48

[1942]4-[3-(2,2-difluoroethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol

[1943] white powder

[1944] MS (ESI+) : m/z 347 (M+H)

[1945] 1HNMR (200MHz, DMSOd6): 3.76 (3H, s), 4.43 (2H, dt, J =3.5,14.9Hz)), 6.08 ( 1H, s), 6.40 (1H, tt, J=3.5, 54.6 Hz)), 6.71 ( 2H, d, J=8.6 Hz) ), 6.92 (2H, d, J =9.0 Hz) ), 7.02 (2H, d, J =8.6 Hz) ), 7.14(2H, d, J =9.0 Hz)

[1946] Preparation 49

[1947]4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]phenol

[1948] white powder

[1949] MS (ESI+) : m/z 366 (M+H)

[1950] 1HNMR (200 MHz, CDCl3): 3.92 (3H, s), 4.61 ( 1H, d, J =8.5 Hz) ),4.69 (1H, d, J =8.5 Hz) ), 5.39 (1H, brs), 5.97 1H, s), 6.72 (1H, d, J=8.9 Hz)), 6.76 (2H, d, J =8.5 Hz)), 7.09 (2H, d, J =8.5 Hz) ), 7.51(1H, dd, J =2.7 ,8.9 Hz)), 8.01 (1H, d, J =2.7 Hz)

[1951] Preparation 50

[1952]4-[3-(2,2-difluoroethoxy)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenol

[1953] white powder

[1954] MS (ESI+) : m/z 348 (M+H)

[1955] 1HNMR (200 MHz, CDCl3): 3.92 (3H, s), 4.46 (2H, dt, J =4.2 ,13.5Hz)), 5.42 (1H, brs), 5.93 (1H, s), 6.16 ( 1H, tt, J =4.2, 55.4 Hz) ),6.72 ( 1H, d, J =8.7 Hz) ), 6.76 (2H, d, J =8.6 Hz) ), 7.09 (2H, d, J=8.6 Hz) ), 7.51 (1H, dd, J =2.7 ,8.7 Hz)), 8.01 (1H, d, J =2.7 Hz)

[1956] Preparation 51

[1957] 4-[1-(4-methoxyphenyl)-4-methyl-1H-pyrazol-5-yl]phenol

[1958] white powder

[1959] MS (ESI+) : m/z 281 (M+H)

[1960] 200 MHz 1HNMR (DMSO-d6, d) :2.00 (3H, s) , 3.74 (3H, s) , 6.74(2H, d, J=8.5 Hz)), 6.88 (2H, d, J=9.0 Hz)), 6.96 (2H, d, J=8.5 Hz)),7.09 (2H, d, J=9.0 Hz)), 7.53 (1H, s), 9.66 (1H, s)

[1961] Preparation 52

[1962] 4-[1-(6-methoxy-3-pyridinyl)-4-methyl-1H-pyrazol-5-yl]phenol

[1963] white powder

[1964] MS (ESI+) : m/z 282 (M+H)

[1965] 1HNMR (200 MHz, DMSOd6) : 2.01 (3H, s), 3.83 (3H, s), 6.75 - 6.85(3H, m), 7.01 (2H, d, J =8.6 Hz) ), 7.53 (1H, dd, J =2.7 ,8.8 Hz)), 7.6(1H, s), 7.96 (1H, d, J =2.7 Hz) ), 9.73 (1H, brs)

[1966] Preparation 53

[1967] To a solution of 4′-benzyloxypropiophenone (6.0 g) in THF (120mg) at −60° C. was added 38 mg of 1N lithium bis(trimethylsilyl)amide(LiHMDS), and the mixture was stirred at under −60° C. for 45 mins.1-(Trifluoroacetyl)-imidazole (3.4 mg) was added and the mixture wasstiired at −60° C. for 1 hour and at 0° C. for 30 min. The ractionmixture was quenched with 0.5N HCl, the mixture was poured into EtOAcand water, and the EtOAc layer was separated, washed with brine, diedover MgSO4, and concentrated to give1-[4-(benzyloxy)phenyl]-4,4,4-trifluoro-2-methyl-1,3-butanedione.

[1968] MASS (ESI+): m/z =359.2 (m+Na).

[1969] 1HNMR (400 MHz, CDCl3): 1.36 (1H, d, J =7.2 Hz)), 1.52 (2H, d, J=7 Hz) ), 5.16 (2H, s), 7.02-7.08 (2H, m), 7.37 -7.44 (5H, m), 7.92 -7.98 (2H, m).

[1970] Preparation 54

[1971] To a mixture of 4-(methylthio)aniline (6.3 g) and conc.HCl (45mg) was added dropwise NaNO2 (3.6 g) in water (18 mg) under ice-coling.After stirring for 30 min., SnC1H2O (28.6 g) in conc.HCl (24 mg) wasadded under ice cooling over 1 hour. After stirring for 1 hour,filtrate, washed with conc.HCl and water, and dried to give 14.1 g of[4-(methylthio)phenyl]hydrazine hydrochloride as a solid.

[1972] MASS (ESI+): m/z =139.3 (M-NH2+1).

[1973] 1HNMR (400 MHz, DMSOd6): 2.42 (3H, s), 3.75 (2H, b.s), 6.97 (2H,d, J =8.7 Hz) ), 7.24 (2H, d, J =8.7 Hz) ), 10.24 (1H, b.s).

[1974] Preparation 55

[1975] A mixture of 4-hydroxypropiophenone (20 g), benzyl chloride (16.1ml), K2CO3 (12.9 g) and KI (2.21 g) in EtOH (80 mg) and H2O (1 ml) wasstirred under reflux condition for 4 hours. The reaction mixture wascooled and filtered. Appeared crystal was dissovled with EtOAc andwater. Organic layer was separated and washed with water and brine,dried over MgSO4 and filtered. Filtrate was evaporated under reducedpressure to give 30.0 g (94%) of 1-[4-(benzyloxy)phenyl]-1-propanone asa crystal.

[1976] MASS (ESI+): m/z =263.2 (M+Na).

[1977] 1HNMR (400 MHz, CDCl3): 1.21 (3H, t, J =7.3 Hz)), 2.95 (2H, q, J=7.3 Hz) ), 5.13 (2H, s), 7 (2H, d, J =8.9 Hz) ), 7.34 - 7.45 (5H, m),7.95 (2H, d, J =8.9 Hz).

[1978] Preparation 56

[1979] 1M NaOH (4.8 mg) was added to a solution of4-benzyloxybenzaldehyde (5 g) and cyclopropyl methyl ketone (3.96 g) inEtOH (24 mg) and the mixture was stirred at ambient temperatureovernight. The reaction mixture was diluted with H2O and EtOH. Themixture was stirred at ambient temperature for 20 minutes. Pale yellowcrystals were collected and washed with H2O and 50% aqueous EtOH to give(2E)-3-[4-(benzyloxy)phenyl]-1-cyclopropyl-2-propen-1-one (6.29 g).

[1980] Pale yellow crystals

[1981] MS (ESI+) : m/z 301 (M+Na)

[1982] 1HNMR (200 MHz, CDCl3): 0.9-1.00 (2H, m), 1.11-1.19 (2H, m),2.16-2.29 (1H, m), 5.11 (2H, s), 6.77 (1H, d, J =16.1 Hz) ), 6.99 (2H,d, J =8.8 Hz) ), 7.32-7.46 (4H, m), 7.52 (2H, d, J=8.8 Hz) ), 7.58 (2H,d, J =16.1 Hz)

[1983] Preparation 57

[1984] (2E)-3-[4-(Benzyloxy)phenyl]-1-cyclopropyl-2-propen-1-one 6.25 g)was suspended in EtOH (67.5 mg), acetone (22.5 mg) To this mixture wasadded hydrogen peroxide 30% aqueous solution (4.5 mg), and 3M NaOH (4.5mg), and the mixture was stirred at ambient temperature for lday. Themixture was diluted with H2O. White precipitates were collected andwashed with H2O, and air dried to give{(2R,3S)-3-[4-(benzyloxy)phenyl]-2-oxiranyl}(cyclopropyl)methanone (6.27g).

[1985] powder

[1986] MS (ESI+) : m/z 317 (M+Na)

[1987] 1HNMR (200 MHz, DMSOd6) : 0.96-1.07 (2H, m), 1.12-1.19 (2H, m),2.11-2.22 (1H, m), 3.59 (1H, d, J 1.8 Hz), 4.04 (1H, d, J 1.8 Hz) 5.08(2H, s), 6.97 (2H, d, J =8.8 Hz), 7.23 (2H, d, J =8.8 Hz) ), 7.35-7.43(5H, m)

[1988] Preparation 58

[1989] To a solution of 4-[3-methoxy-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenol (501 mg) in CH2Cl2 (5 mg) was added trifluoromethanesulfonicanhydride (300 μl) and diisopropylethylamine (324 μl) under ice-bathcooling. The mixture was stirred at same temperature for 2 hours.Additional trifluoromethanesulfonic anhydride (57 μl) anddiisopropylethylamine (147 μl) were added and stirring at sametemperature was continued for 1 hour. The mixture was washed with 1MHCl, saturated aqueous sodium bicarbonate solution and saturated aqueoussodium chloride solution, dried over magnesium sulfate, and concentratedin vacuo. The residue was purified by silica gel column chromatographyeluted with AcOEt/n-hexane =20% to give4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenyltrifluoromethanesulfonate (712.3 mg) as an oil.

[1990] MS (ESI+) : m/z 429 (M+H)

[1991] 1HNMR (200 MHz, CDCl3) : 3.81 (3H, s) , 3.98 (3H, s), 5.97 1H,s), 6.85 (2H, d, J =9.0 Hz) ), 7.11-7.32 (6H, m)

[1992] The following compound(s) was(were) obtained in a similar mannerto that of Preparation 58.

[1993] Preparation 59

[1994] 4-[3-isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenyltrifluoromethanesulfonate

[1995] oil

[1996] MS ESI+) : m/z 457 (M+H)

[1997] 1HNMR (200 MHz, CDC13) : 1.40 (6H, d, J=6.2 Hz)), 3.81 (3H, s),4.89 (1H, m) , 5.94 (1H, s), 6.84 (2H, d, J =9.0 Hz) 7.14 (2H, d, J =9.0Hz) ), 7.20-7.32 (4H, m)

[1998] Preparation 60

[1999] 4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenyltrifluoromethanesulfonate

[2000] oil

[2001] MS (ESI+) : m/z 433 (M+H)

[2002] 1HNMR (200 MHz, CDCl3): 3.82 (3H, s) , 6.46 (1H, s), 6.86 (2H, d,J =9.0 Hz) ), 7.17 (2H, d, J =9.0 Hz) ), 7.23-7.32 (4H, m)

[2003] Preparation 61

[2004] A mixture of4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenyltrifluoromethanesulfonate (679 mg), zinc cyanide (279 mg), andtetrakis(triphenylphosphine)-palladium(0) (183 mg) in DMF (4 mg) wasstirred at 85° C. for 5 hours. The reaction mixture was cooled toambient temperature and AcOEt and H2O were added. Unsoluble matter wasfiltered off through a celite pad. The filtrate was partitioned, and theorganic layer was washed with saturated aqueous sodium chloridesolution, dried over magnesium sulfate, and concentrated invacuo. Theresidue was purified by silica gel column chromatography eluted withAcOEt/n-hexane =20%. The pure fractions were collected and concentratedin vacuo to give 4-[3-methoxy-1-(4-methoxy-phenyl)-1-H-pyrazol-5-yl]benzonitrile (326 mg) as a powder.

[2005] mp.112-113° C.

[2006] MS (ESI+) : m/z 306 (M+H), 328 (M+Na)

[2007] IR (KBr) : 2929, 2227, 1568, 1552, 1541, 1518 cm−1

[2008] 1HNMR (200 MHz, CDCl3) : 3.81 (3H, s) , 3.98 (3H, s) , 6.01 (1H,s), 6.85 (2H, d, J =8.9 Hz) ) , 7.15 (2H, d, J =8.9 Hz) 7.30 (2H, d, J=8.5 Hz) ), 7.57 (2H, d, J =8.5 Hz)

[2009] The following compound(s) was(were) obtained in a similar mannerto that of Preparation 61.

[2010] Preparation 62

[2011] 4-[3-isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-benzonitrile

[2012] mp. 96-97° C.

[2013] MS (ESI+) : m/z 334 (M+H), 356 (M+Na)

[2014] 1HNMR (200 MHz, CDCl3): 1.40 (6H, d, J =6.1 Hz)), 3.81 (3H, s) ,4.89 (1H, m) , 5.98 (1H, s) , 6.84 (2H, d, J =9.0 Hz), 7.14 (2H, d, J=9.0 Hz) ), 7.30 (2H, d, J =8.6 Hz), 7.56 (2H, d, J =8.6 Hz)

[2015] Preparation 63

[2016]4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1-H-pyrazol-5-yl]benzonitrile

[2017] oil

[2018] MS (ESI+) : m/z 375 (M+H)

[2019] 1HNMR (200 MHz, CDCl3): 3.94 (3H, s), 4.62 (1H, d, J =8.4 Hz)),4.71 (1H, d, J =8.4 Hz)), 6.12 (1H, s), 6.76 (1H, d, J =8.7 Hz) ), 7.33(2H, d, J 8.4 Hz) ), 7.5 (1H, dd, J =2.7, 8.7 Hz), 7.62 (2H, d, J =8.4Hz) ), 7.97 (1H, d, J =2.7 Hz)

[2020] Preparation 64

[2021] 4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-benzonitrile

[2022] powder

[2023] MS (ESI+) : m/z 310 (M+H), 332 (M+Na)

[2024] 1HNMR (200 MHz, CDCl3): 3.83 (3H, s), 6.50 (1H, s), 6.87 (2H, d,J =9.0 Hz) ), 7.16 (2H, d, J =9.0 Hz), 7.30 (2H, d, J =8.5 Hz), 7.60(2H, d, J =8.5 Hz)

[2025] Preparation 65

[2026]4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]-benzonitrile

[2027] powder

[2028] MS (ESI+) : m/z 311 (M+H), 333 (M+Na)

[2029] 1HNMR (200 MHz, CDCl3): 3.94 (3H, s), 6.53 (1H, s), 6.78 (1H, d,J =8.9 Hz) ), 7.33 (2H, d, J =8.4 Hz) ), 7.54 (1H, dd, J =2.7 ,8.9 Hz),7.64 (2H, d, J =8.4 Hz) ), 7.99 (1H, d, J =2.7 Hz)

[2030] Preparation 66

[2031] A solution of trifluoromethanesulfonic anhydride (207 μl) inCH2Cl2 (1 ml) was added to a solution of4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1-H-pyrazol-5-yl]phenol(300 mg) and pyridine (199 μl) in CH2C12 (3 mg) inder ice-bath cooling.The mixture was stirred at same temperature for 1 hour. The reaction wasquenched by adding saturated aqueous ammonium chloride solution (5 mg)The mixture was partitioned between AcOEt and 1M HCl. The mixture waswashed with saturated aqueous sodiumbicarbonate solution and saturatedaqueous sodium chloride solution, dried over magnesium sulfate, andconcentrated in vacuo to give4-[l-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoro-ethoxy)-1-H-pyrazol-5-yl]phenyltrifluoromethane-sulfonate (439 mg) as an oil.

[2032] MS (ESI+) : m/z 498 (M+H)

[2033] 1HNMR (200 MHz, CDCl3): 3.94 (3H, s), 4.62 (1H, d, J =8.4 Hz) ),4.71 (1H, d, J =8.4 Hz) ), 6.08 (1H, s), 6.74 (1H, d, J =8.7 Hz) ),7.22-7.38 (4H, m), 7.47 (1H, dd, J =2.7, 8.7 Hz), 8.01 (1H, d, J =2.7Hz)

[2034] The following compound(s) was (were) obtained in a similar mannerto that of Preparation 66.

[2035] Preparation 67

[2036] 4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]-phenyltrifluoromethanesulfonate

[2037] oil

[2038] MS (ESI+) : m/z 434 (M+H)

[2039] 1HNMR (200 MHz, CDCl3): 3.94 (3H, s), 6.49 (1H, s), 6.76 (1H, d,J =8.9 Hz) ), 7.23-7.34 (4H, m), 7.52 (1H, dd, J =2.8 , 8.9 Hz), 8.02(1H, d, J =2.8 Hz)

[2040] Preparation 68

[2041] A solution of4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenyl benzyl ether(2.79 g) and thioanisole (3.56 g) intrifluoroacetic acid (25 mg) wasstirred at ambient temperature overnight. The mixture was concentratedin vacuo. The residue was recrystallized from AcOEt (15 mg) and n-hexane(12 mg) to givr 1st crop of FR282117 (1.48 g). The mother liqour waswashed with H2O, saturated aqueous sodium chloride solution, dried overmagnesium sulfate, and concentrated in vacuo. The residue was purifiedby silica gel column chromatography eluted with AcOEt/n-hexane =30%. Thepure fractions were collected and concentrated in vacuo. The residualcrystals were collected and washed with IPE to give 2nd crop of4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol(457.2 mg) whitepowder

[2042] Mass (ESI+) : m/z 301 (M+H)

[2043] 200 MHz 1HNMR(DMSO-d6, d) : 3.78 (3H, s), 6.62 (1H, s), 6.71 (2H,d, J=8.7 Hz)), 6.96 (2H, d, J=9.0 Hz), 7.03 (2H, d, J=8.7 Hz), 7.19 (2H,d, J=9.0 Hz), 9.80 (1H, s)

[2044] The following compound(s) was(were) obtained in a similar mannerto that of Preparation 68.

[2045] Preparation 69

[2046] 4-[1-(4-methoxyphenyl)-3-(methylthio)-1H-pyrazol-5-yl]-phenol

[2047] powder

[2048] MS (ESI+) : m/z 313 (M+H)

[2049] 1HNMR (200 MHz, DMSOd6): 2.50 (3H, s), 3.77 (3H, s), 6.49 (1H,s), 6.70 (2H, d, J=8.6 Hz)), 6.94 (2H, d, J =9.0 Hz), 7.02 (2H, d, J=8.6 Hz), 7.16 (2H, d, J =9.0 Hz), 9.71 1H, brs)

[2050] The following compound(s) was(were) obtained in a similar mannerto that of Example 596.

[2051] Preparation 70

[2052]4-[1-[4-(methylthio)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenol

[2053] MASS (ESI+): m/z =373.1 (M+Na).

[2054] 1HNMR (400 MHz, CDCl3): 2.49 (3H, s), 5.13 (1H, b.s), 6.67 (1H,s), 6.79 (2H, d, J=8.7 Hz) ), 7.1 (2H, d, J =8.7 Hz), 7.2 (2H, d, J =9.1Hz) ), 7.23 (2H, d, J =9.1 Hz)

[2055] Preparation 71

[2056]4-{3-(difluoromethyl)-1-[4-(methylthio)phenyl]-1H-pyrazol-5-yl}phenol

[2057] MASS (ESI+) m/z =355.1 (M+Na)

[2058] 1HNMR (400 MHz, CDCl3) : 2.49 (3H, s), 5.17 (1H, b.s), 6.65 (1H,s) , 6.76 (1H, t, J =55 Hz)), 6.78 (2H, d, J =8.7 Hz) 7.1 (2H, d, J =8.7Hz) ), 7.2 (4H, s).

[2059] Preparation 72

[2060]4-[1-(6-methoxy-3-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzonitrile

[2061] MASS (ESI+): m/z =345.1, 367.1 (m+H, m+Na).

[2062] 1HNMR (400 MHz, CDC13) : 3.96 (3H, s) , 6.8 (1H, d, J=8.8 Hz)6.85 (1H, s), 7.36 (2H, d, J =8.4 Hz) ), 7.57 (1H, dd, J =2.7 ,8.8 Hz)),7.66 (2H, d, J =8.4 Hz), 8.04 (1H, d, J =2.7 Hz).

[2063] Preparation 73

[2064]4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]benzonitrile

[2065] MASS (ESI+): m/z =327.1 (m+l).

[2066] 1HNMR (400 MHz, CDCl3): 3.95 (3H, s), 6.77 (1H, t, J =54.8 Hz) ),6.79 (1H, d, J =8.8 Hz) ), 6.82 (1H, s), 7.36 (2H, d, J =8.4 Hz), 7.54(1H, dd, J =2.8, 8.8 Hz), 7.65 (2H, d, J =8.4 Hz), 8.04 (1H, d, J =2.8Hz)

[2067] Example 415

[2068] 4M HCl in dioxane (3 mg) was added to a solution of tert-butyl(2-14-[3-(1-hydroxy-1-methylethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxylethyl)-carbamate(236 mg) in CH2Cl2 (3 mg). The reaction mixture was stirred at ambienttemperature for 3 hours. 2-Propanol (2 mg) was added to dissolveunsoluble oil, and stirred at ambient temperature for 4 hours. Themixture was concentrated in vacuo. The residue was suspended in CH2Cl2(3 mg). Methanesulfonyl chloride (127 mg) was added and then Et3N wasadded to adjust pH of the rection mixture to neutral. After stirring for1 hour, the reaction mixture was concentrated in vacuo. The residue waspartitioned between ethyl acetate and water. The mixture was extractedwith ethyl acetate. The organic layer was washed with saturated aqueoussodium bicarbonate solution and saturated aqueous sodium chloridesolution, dried over magnesium sulfate, and concentrated in vacuo. Theresidue was purified by silica gel column chromatography eluted with 50%AcOEt/n-hexane to giveN-(2-14-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)methane-sulfonamide(118 mg) as an oil.

[2069] 1H NMR (CDCl3) δ 2.20 (3H, s), 3.03 (3H, s), 3.51-3.60 (2H, m),3.93 (3H, s), 4.07-4.13 (2H, m), 4.77 (1H, t, J=6.0 Hz)), 5.15 (1H,brs), 5.60 (1H, brs), 6.59 (1H, s), 6.73 (1H, d, J=8.9 Hz), 6.83 (2H, d,J=8.8 Hz)), 7.17 (2H, d, J=8.8 Hz)), 7.55 (1H, dd, J=2.6,8.8 Hz)), 8.09(1H, d, J=2.6 Hz)

[2070] Example 416

[2071] A mixture of 10% Pd-C 50% wet (20 mg) andN-(2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)methanesulfonamide(118 mg) in THF (1 ml) and MeOH (1 ml) was hydrogenated under H2 1atm atambient temperature for 1 day. The catalyst was removed by filtration.The filtrate and combined washings were concentrated in vacuo. Theresidue was purified by preparative thin layer silica gel chromatographydeveloped by AcOEt/n-hexane=70%. The seaparated silica gel was extractedwith 10% MeOH/CHCl3 and the solvent was evaporated in vacuo. The residuewas recrystallized from AcOEt-IPE to giveN-(2-{4-[3-isopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)methanesulfonamide(68.6 mg) as white powder.

[2072] white powder

[2073] mp. 96-97° C.

[2074] IR (KBr) : 3269, 2970, 1612, 1512 cm−1

[2075] MS (ESI+) : m/z 431 (M+H)

[2076] 1H NMR (DMSO-d6) δ 1.27 (6H, d, J=6.9 Hz)), 2.88-2.99 (1H, m),2.92 (3H, s), 3.92-3.35 (2H, m), 3.85 (3H, s), 3.99-4.06 (2H, m), 6.46(1H, s), 6.88 (1H, d, J=8.7 Hz)), 6.94 (2H, d, J=8.8 Hz), 7.17 (2H, d,J=8.8 Hz)), 7.28 (1H, s), 7.60 (1H, dd, J=2.7,8.7 Hz)), 8.02 (1H, d,J=2.7 Hz))

[2077] The following compound(s) was(were) obtained in a similar mannerto that of Example 416.

[2078] Example 417

[2079] tert-butyl{4-[3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}carbamate

[2080] oil

[2081] MS (ESI+) : m/z 422 (M+H)

[2082] 1HNMR (200 MHz, ) : 1.34 (6H, d, J =7.0 Hz) ), 1.46 (9H, s), 3.08(1H, m), 3.80 (3H, s), 4.30 (2H, d, J =5.9 Hz), 4.81 (1H, brs), 6.31(1H, s), 6.83 (2H, d, J =9.0 Hz), 7.15-7.26 (6H, m)

[2083] Example 418

[2084] tert-butyl{4-[3-isopropyl-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]benzyl}carbamate

[2085] oil

[2086] MS (ESI+) : m/z 423 (M+H)

[2087] 1HNMR (200 MHz, CDCl3) 1.34 (6H, d, J =7 Hz), 1.46 (9H, s), 3.07(1H, m), 3.92 (3H, s), 4.30 (2H, d, J=6.0 Hz), 4.84 (1H, brs), 6.33 (1H,s), 6.72 (1H, d, J =8.8 Hz), 7.15-7.26 (4H, m), 7.56 (1H, dd, J =2.7,8.8 Hz), 8.04 1H, d, J =2.7 Hz)

[2088] Example 419

[2089] A 4M solution of HCl in dioxane (2 mg) was added to a solution ofter-butyl(2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)carbamate(269.7 mg) in CH2Cl2 (2 mg) . The reaction mixture was stirred atambient temperature for 2 hours, then, was concentrated in vacuo to give(2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)aminedihydrochloride (259 mg) as an amorphous powder.

[2090] MS (ESI+) : m/z 351 (M+H)

[2091] 1H NMR (DMSO-d6) δ 2.10 (3H, s), 3.15-3.23 (2H, m), 3.86 (3H, s),4.16-4.24 (2H,m), 5.15 (1H,brs), 5.63 (1H,brs), 6.85 (1H, s), 6.86-7.00(3H, m), 7.18-7.25 (2H, m), 7.66 (1H, dd, J=2.8,8.7 Hz), 8.06 (1H, d,J=2.8 Hz), 8.24 (2H, brs)

[2092] The following compound(s) was(were) obtained in a similar mannerto that of Example 419.

[2093] Example 420

[2094](2-{4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy}ethyl)aminehydrochloride

[2095] white powder

[2096] Mass (ESI+) : 340 (M+H)+

[2097] 200 MHz 1HNMR (DMSO-d6, d) : 3.16-3.23 (2H, m), 3.76 (3H, s),3.84 (3H, s), 4.14-4.20 (2H,m), 6.06 (1H,s),6.93 (2H,d, J=8.9 Hz), 6.94(2H, d, J=8.7 Hz)), 7.14 (2H, d, J=8.9 Hz), 7.17 (2H, d, J=8.7 Hz), 8.16(2H, brs)

[2098] Example 421

[2099](2-{4-[3-ethoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy}ethyl)aminehydrochloride

[2100] white powder

[2101] Mass (ESI+) : 354 (M+H)+

[2102] 200 MHz 1H NMR (DMSO-d6, d) : 1.33 (3H, t, J=7.0 Hz), 3.14-3.23(2H, m), 3.76 (3H, s), 4.12-4.23 (4H, m), 6.04 (1H, s), 6.92 (2H, d,J=9.0 Hz), 6.94 (2H, d, J=8.8 Hz), 7.12 (2H, d, J=9.0 Hz), 7.16 (2H, d,J=8.8 Hz), 8.24 (2H, brs)

[2103] Example 422

[2104](2-{4-[3-isobutoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)aminehydrochloride

[2105] amorphous

[2106] Mass (ESI+) : 382 (M+H)+

[2107] 200 MHz 1H NMR (DMSO-d6, d) : 0.97 (6H, d, J=6.7 Hz), 2.03 (1H,m), 3.14-3.23 (2H, m), 3.76 (3H, s), 3.90 (2H, d, J=6.6 Hz), 4.14-4.20(2H,m), 6.06 (1H,s), 6.92 (2H,d,J=9.0 Hz), 6.94 (2H, d, J=8.8 Hz),7.08-7.19 (4H, m), 8.23 (2H, brs)

[2108] Example 423

[2109](2-{4-[3-(2-methoxyethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)aminehydrochloride

[2110] amorphous

[2111] Mass (ESI+) : 384 (M+H)+

[2112] 200 MHz 1H NMR (DMSO-d6, d) : 3.15-3.23 (2H, m), 3.31 (3H, s),3.62-3.67 (2H, m), 3.75 (3H, s), 4.14-4.27 (4H, m), 6.06 (1H, s), 6.92(2H, d, J=8.9 Hz), 6.95 (2H, d, J=8.8 Hz), 7.13 (2H, d, J=8.9 Hz), 7.17(2H, d, J=8.8 Hz), 8.20 (2H, brs)

[2113] Example 424

[2114](2-{4-[3-(2-ethoxyethoxy)-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)aminehydrochloride

[2115] amorphous

[2116] Mass (ESI+) : 398 (M+H)+

[2117] 200 MHz 1H NMR (DMSO-d6, d) : 1.13 (3H, t, J=7.0 Hz), 3.15-3.24(2H, m), 3.50 (2H, q, J=7.0 Hz), 3.66-3.71 (2H, m), 3.76 (3H, s),4.13-4.27 (4H,m), 6.07 (1H, s), 6.93 (2H, d, J=8.9 Hz), 6.95 (2H, d,J=8.7 Hz), 7.13 (2H, d, J=8.9 Hz)), 7.17 (2H, d, J=8.7 Hz), 8.13 (2H,brs)

[2118] Example 425

[2119](2-{4-[3-methoxy-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenoxy)ethyl)aminedihydrochloride

[2120] amorphous

[2121] MS (ESI+) : m/z 341 (M+H)+

[2122] 200 MHz 1HNMR (DMSO-d6, d): 3.16-3.23 (2H, m), 3.84 (3H, s), 3.85(3H, s), 4.16-4.21 (2H,m), 6.12 (1H, s), 6.86 (1H, d, J=8.7 Hz), 6.98(2H, d, J=8.7 Hz), 7.21 (2H, d, J=8.7 Hz)), 7.62 (1H, dd, J=2.5, 8.7Hz), 7.99 (1H, d, J=2.5 Hz), 8.24 (2H, brs)

[2123] Example 426

[2124](2-{4-[3-ethoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)aminedihydrochloride

[2125] amorphous

[2126] MS (ESI+) : m/z 355 (M+H)+

[2127] 200 MHz 1H NMR (DMSO-d6, d) : 1.33 (3H, t, J=7.0 Hz), 3.15-3.24(2H, m), 3.84 (3H, s), 4.13-4.24 (2H, m), 4.19 (2H, q, J=7.0 Hz), 6.10(1H, s), 6.86 (1H, d, J=8.9 Hz), 6.98 (2H, d, J=8.8 Hz), 7.21 (2H, d,J=8.8 Hz), 7.60 (1H, dd, J=2.7, 8.9 Hz), 7.98 (1H, d, J=2.7 Hz), 8.19(2H, brs)

[2128] Example 427

[2129](2-{4-[1-(4-methoxyphenyl)-4-methyl-3-(trifluoro-methyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)amine

[2130] hydrochloride

[2131] MASS (ESI+): m/z =392.2 (M+H).

[2132] 1HNMR (400 MHz, DMSOd6): 2.09 (3H, s), 3.1-3.3 (2H, m), 3.36 (2H,b.s), 3.57 (3H, s), 4.20 (2H, t, J =5 Hz), 6.94 (2H, d, J =8.9 Hz), 7.01(2H, d, J =8.8 Hz), 7.2 (2H, d, J =8.9 Hz) ), 7.21 (2H, d, J =8.8 Hz),8.29 (2H, br.s).

[2133] Example 428

[2134](2-{4-[1-[4-(methylthio)phenyl]-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenoxy}ethyl)aminehydrochloride

[2135] MASS (ESI+): m/z =394.1 (M(Free)+1, HCl salt).

[2136] 1HNMR (200 MHz, DMSOd6): 2.5 (3H, s), 3.15-3.25 (2H, m), 4.22(2H, t, J =5 Hz), 7 (2H, d, J =8.7 Hz), 7.1 (1H, s), 7.26 (2H, d, J =8.7Hz), 7.27 (2H, d, J =9.8 Hz) 7.33 (2H, d, J =9.8 Hz), 8.35 (2H, b.s).

[2137] Example 429

[2138][2-(4-{3-(difluoromethyl)-1-[4-(methylthio)phenyl]-1H-pyrazol-5-yl}phenoxy)ethyl]aminehydrochloride

[2139] MASS (ESI-): m/z =410.0 (M-1).

[2140] 1HNMR (400 MHz, DMSOd6): 2.49 (3H, s), 3.2 (2H, t, J =5 Hz) ),4.19 (2H, t, J =5 Hz) ), 6.87 (1H, s), 6.99 (1H, d, J =8.7 Hz), 7.09(1H, t,J =53.5 Hz), 7.24 (4H, d, J =9.6 Hz), 7.3 (2H, d, J =8.7 Hz),8.17 (2H, b.s).

[2141] Example 430

[2142](2-{4-[3-cyclopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)aminedihydrochloride

[2143] amorphous powder

[2144] MS (ESI+) : m/z 351 (M+H)

[2145] 1HNMR (200 MHz, DMSOd6): 0.70- 0.78 (2H, m), 0.86-1.02 (2H, m),1.88-1.99 (1H, m), 3.10-3.20 (2H, m), 3.85 (3H, s), 4.15-4.21 (2H, m),6.31 (1H, s), 6.86 (1H, d, J =8.9 Hz), 6.96 (2H, d, J =8.8 Hz), 7.17(2H, d, J =8.8 Hz), 7.60 (1H, dd, J =2.7, 8.9 Hz), 8.00 (1H, d, J =2.7Hz), 8.24 (2H, brs)

[2146] Example 431

[2147](2-{4-[1-(4-methoxyphenyl)-3-(1-piperidinylcarbonyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)aminehydrochloride

[2148] amorphous powder

[2149] MS (ESI+) : m/z 421 (M+H)

[2150] 1HNMR (200 MHz, DMSOd6): 1.43-1.72 (6H, m) , 3.14-3.24 (2H, m),3.52-3.70 (2H, m), 3.77-3.95 (2H, m), 3.78 (3H, s), 4.15-4.20 (2H, m),6.79 (1H, s), 6.96 (2H, d, J =8.8 Hz), 6.99 (2H, d, J =8.9 Hz), 7.21(2H, d, J =8.8 Hz), 7.24 (2H, d, J =8.9 Hz) ), 8.14 (2H, brs)

[2151] Example 432

[2152](2-{4-[1-(6-methoxy-3-pyridinyl)-3-(1-piperidinyl-carbonyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)amine

[2153] dihydrochloride

[2154] amorphous powder

[2155] MS (ESI+) : m/z 422 (M+H)

[2156] 1HNMR (200 MHz, CDCl3): 1.42-1.75 (6H, m), 3.14-3.24 (2H, m),3.52-3.70 (2H, m), 3.73-3.94 (2H, m), 3.87 (3H, s), 4.16-4.22 (2H, m),6.83 (1H, s), 6.91 (1H, d, J =8.9 Hz), 6.99 (2H, d, J =8.8 Hz), 7.25(2H, d, J =8.8 Hz), 7.69 (1H, dd, J =2.7 ,8.9 Hz), 8.14 (1H, d, J =2.7Hz), 8.21 (2H, brs)

[2157] Example 433

[2158]5-[4-(2-aminoethoxy)phenyl]-N-ethyl-1-(6-methoxy-3-pyridinyl)-N-methyl-1-H-pyrazole-3-carboxamide

[2159] dihydrochloride

[2160] amorphous powder

[2161] Mass (ESI+) : m/z 396 (M+H)

[2162] 1HNMR (200 MHz, DMSOd6): 1.09-1.23 (3H, m)), 2.98, 3.29 (3H, s),3.13-3.25 (2H, m), 3.43-3.78 (4H, m), 3.87 (3H, s), 4.16-4.22 (2H, m),6.84, 6.86 (1H, s), 6.91 3 (1H, d, J =8.7 Hz) ), 7 .00 (2H, d, J =8.7Hz) ), 7.25 (2H, d, J =8.7 Hz), 7.61-7.74 (1H, m), 8.13-8.20 (3H, m)

[2163] Example 434

[2164](2-{4-[3-(cyclopentyloxy)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)aminedihydrochloride

[2165] amorphous powder

[2166] MS (ESI+) : m/z 395 (M+H)

[2167] 1HNMR (400 MHz, DMSOd6): 1.57-1.91 (8H, m), 3.16-3.21 (2H, m),3.84 (3H, s), 4.17-4.21 (2H, m), 4.95-5 (1H, m), 6.08 (1H, s), 6.85 (1H,d, J =8.8 Hz), 6.98 (2H, d, J =8.8 Hz), 7.2 (2H, d, J =8.8 Hz), 7.59(1H, dd, J =2.8 ,8.8 Hz), 7.98 (1H, d, J =2.8 Hz), 8.24 (2H, brs)

[2168] Example 435

[2169](2-{4-[1-(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1-H-pyrazol-5-yl]phenoxylethyl)aminehydrochloride

[2170] oil

[2171] MS (ESI+) : m/z 408 (M+H)

[2172] 1HNMR (200 MHz, DMSOd6): 3.13-3.24 (2H, m), 3.76 (3H, s),4.15-4.21 (2H, m), 4.82 (1H, d, J =9.0 Hz), 4.91 (1H, d, J =9.0 Hz),6.23 (1H, s), 6.92-6.99 (4H, m), 7.13-7.21 (4H, m), 8.20 (2H, brs)

[2173] Example 436

[2174](2-{4-[3-(2,2-difluoroethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)aminehydrochloride

[2175] amorphous powder

[2176] MS (ESI+) : m/z 390 (M+H)

[2177] 1HNMR (200 MHz, DMSOd6): 3.13-3.23 (2H, m), 3.76 (3H, s),4.14-4.20 (2H, m), 4.44 (2H, dt, J =3.5 , 14.9 Hz), 6.16 (1H, s), 6.41(1H, tt, J =3.5, 54.6 Hz), 6.94 (2H, d, J =8.9 Hz), 6.95 (2H, d, J =8.9Hz), 7.16 (2H, d, J =8.9 Hz), 7.18 (2H, d, J =8.9 Hz), 8.17 (2H, brs)

[2178] Example 437

[2179](2-{4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoro-ethoxy)-1H-pyrazol-5-yl]phenoxy}ethyl)amine

[2180] dihydrochloride

[2181] amorphous powder

[2182] MS (ESI+) : m/z 409 (M+H)

[2183] 1HNMR (200 MHz, DMSOd6): 3.16-3.21 (2H, m), 3.85 (3H, s),4.16-4.22 (2H, m), 4.83 (1H, d, J =9.0 Hz), 4.92 1H, d, J=9.0 Hz), 6.29(1H, s), 6.88 (1H, d, J=8.8 Hz), 6.99 (2H, d, J =8.8 Hz), 7.22 (2H, d, J=8.8 Hz), 7.63 (1H, dd, J =2.7 ,8.8 Hz), 8.03 (1H, d, J =2.7 Hz), 8.19(2H, brs)

[2184] Example 438

[2185](2-{4-[3-(2,2-difluoroethoxy)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenoxylethyl)amine

[2186] dihydrochloride

[2187] powder

[2188] MS (ESI+) : m/z 391 (M+H)

[2189] 1HNMR (200 MHz, DMSOd6) : 3.15-3.24 (2H, m), 3.85 (3H, s),4.16-4.22 (2H, m), 4.46 (2H, dt, J =3.5 ,14.9 Hz), 6.22 (1H, s), 6.42(1H, tt, J =3.5, 54.5 Hz), 6.87 (1H, d, J =8.9 Hz), 6.99 (2H, d, J =8.7Hz), 7.22 (2H, d, J =8.7 Hz), 7.62 (1H, dd, J =2.7 ,8.9 Hz), 8.02 (1H,d, J =2.7 Hz), 8.20 (2H, brs)

[2190] Example 439

[2191]{4-[1-(4-methoxyphenyl)-3-(1-piperidinylcarbonyl)-1H-pyrazol-5-yl]benzyllaminehydrochloride

[2192] amorphous powder

[2193] MS (ESI+) : m/z 391 (M+H)

[2194] 1HNMR (200 MHz, DMSOd6): 1.43-1.74 (6H, m) , 3.51-3.72 (2H, m),3.77-3.93 (2H, m), 3.79 (3H, s), 3.97-4.06 (2H, m), 6.90 (1H, s), 6.99(2H, d, J =8.9 Hz), 7.26 (2H, d, J =8.9 Hz), 7.30 (2H, d, J =8.2 Hz),7.46 (2H, d, J =8.2 Hz), 8.38 (2H, brs)

[2195] Example 440

[2196]5-[4-(aminomethyl)phenyl]-N-ethyl-1-(4-methoxyphenyl)-N-methyl-1-H-pyrazole-3-carboxamidehydrochloride

[2197] powder

[2198] MS (ESI+) : m/z 365 (M+H)

[2199] 1HNMR (200 MHz, DMSOd6) : 1.09-1.22 (3H, m), 2.98, 3.29 3H, s),3.35-3.80 (2H, m), 3.79 (3H, s), 3.97 -. 4.08 2H, m), 6.91, 6.93 (1H,s), 6.99 (2H, d, J =8.9 Hz), 7.26 (2H, d, J=8.9 Hz), 7.30 (2H, d, J =8.3Hz), 7.46 (2H, d, J =8.3 Hz), 8.37 (2H, brs)

[2200] Example 441

[2201] {4-[3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-benzyl}aminehydrochloride

[2202] oil

[2203] MS (ESI+) : m/z 322 (M+H)

[2204] 1HNMR (200 MHz, DMSOd6): 1.27 (6H, d, J =6.8 Hz), 2.96 (1H, m),3.77 (3H, s), 3.95-4.03 (2H, m), 6.51 (1H, s), 6.94 (2H, d, J =8.9 Hz),7.17 (2H, d, J =8.9 Hz), 7.25 (2H, d, J =8.2 Hz), 7.45 (2H, d, J =8.2Hz), 8.45 (2H, brs)

[2205] Example 442

[2206]1-[5-[4-(aminomethyl)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-2-methyl-1-propanonehydrochloride

[2207] amorphous powder

[2208] MS (ESI+) : m/z 350 (M+H)

[2209] 1HNMR (200 MHz, DMSOd6): 1.16 (6H, d, J =6.9 Hz), 3.68 (1H, m),3.80 (3H, s), 4.01 (2H, s), 7.01 (2H, d, J =8.9 Hz), 7.10 (1H, s), 7.267.34 (4H, m), 7.46 (2H, d, J =8.2 Hz), 8.33 (2H, brs)

[2210] Example 443

[2211]{4-[1-(6-methoxy-3-pyridinyl)-3-(1-piperidinyl-carbonyl)-1-H-pyrazol-5-yl]benzyl}aminedihydrochloride

[2212] oil

[2213] MS (ESI+) : m/z 392 (M+H)

[2214] 1HNMR (200 MHz, DMSO-d6): 1.45 -1.73 (6H, m), 3.53 -3.70 (2H, m),3.70-3.98 (2H, m), 3.98-4.08 (2H, m), 6.92 (1H, d, J =8.8 Hz), 6.93 (1H,s), 7.32-7.55 (4H, m), 7.74 (1H, dd, J =2.7 ,8.8 Hz), 8.15 (1H, d, J=2.7 Hz), 8.38 (2H, brs)

[2215] Example 444

[2216]5-[4-(aminomethyl)phenyl]-N-ethyl-1-(6-methoxy-3-pyridinyl)-N-methyl-1-H-pyrazole-3-carboxamide

[2217] dihydrochloride

[2218] oil

[2219] MS (ESI+) : m/z 366 (M+H)

[2220] 1HNMR (200 MHz, DMSOd6): 1.09-1.23 (3H, m) , 2.98, 3.29 (3H, s),3.43-3.77 (2H, m), 3.88 (3H, s), 3.97-4.06 (2H, m), 6.89-6.96 (2H, m),7.32-7.80 (5H, m), 8.14-8.16 (1H, m), 8.52 (2H, brs)

[2221] Example 445

[2222]{4-[3-isopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]benzyl}aminedihydrochloride

[2223] amorphous powder

[2224] MS (ESI+) : m/z 323 (M+H)

[2225] 1HNMR (200 MHz, DMSOd6): 1.28 (6H, d, J =6.9 Hz), 2.86-3.05 (1H,m), 3.85 (3H, s), 3.96-4.06 (2H, m), 6.57 1H, s), 6.88 (1H, d, J =8.8Hz), 7.26-7.53 (4H, m), 7.66 (1H, dd, J =2.7 ,8.8 Hz), 8.02 (1H, d, J=2.7 Hz), 8.48 (2H, brs)

[2226] Example 446

[2227]1-[5-[4-(aminomethyl)phenyl]-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-3-yl]-2-methyl-1-propanonedihydrochloride

[2228] oil

[2229] MS (ESI+) : m/z 351 (M+H)

[2230] 1HNMR (200 MHz, DMSOd6): 1.17 (6H, d, J =6.8 Hz), 3.68 (1H, m),3.89 (3H, s), 3.98-4.06 (2H, m), 6.95 (1H, d, J=8.8 Hz), 7.13 (1H, s),7.36 (2H, d, J =8.2 Hz), 7.51 (2H, d, J =8.2 Hz), 7.80 (1H, dd, J =2.7,8.8 Hz), 8.19 (1H, d, J =2.7 Hz), 8.43 (2H, brs)

[2231] Example 447

[2232](2-{4-[1-(4-methoxyphenyl)-4-methyl-1H-pyrazol-5-yl]-phenoxy}ethyl)aminehydrochloride

[2233] powder

[2234] MS (ESI+) : m/z 324 (M+H)

[2235] 200 MHz 1H NMR (DMSO-d6, d) : 2.02 (3H, s), 3.17-3.26 (2H, m),3.74 (3H,s),4.13-4.19 (2H,m), 6.89 (2H,d,J=9.0 Hz), 6.98 (2H, d, J=8.7Hz), 7.10 (2H, d, J=8.9 Hz), 7.13 (2H, d, J=8.7 Hz), 7.57 (1H, s), 8.05(2H, brs)

[2236] Example 448

[2237](2-{4-[1-(6-methoxy-3-pyridinyl)-4-methyl-1H-pyrazol-5-yl]phenoxy}ethyl)aminedihydrochloride

[2238] oil

[2239] MS(ESI+) : m/z 325 (M+H)

[2240] 1HNMR (200 MHz, DMSOd6): 2.03 (3H, s), 3.16-3.24 (2H, m), 3.83(3H, s), 4.18-4.24 (2H, m), 6.84 (1H, d, J =8.7 Hz), 7.01 (2H, d, J =8.8Hz), 7.17 (2H, d, J =8.8 Hz), 7.56 (1H, dd, J =2.7 ,8.7 Hz), 7.64 (1H,s), 7.98 (1H, d, J =2.7 Hz), 8.28 (2H, brs)

[2241] Example 449

[2242](2-{4-[1-(4-methoxyphenyl)-3-(methylthio)-1H-pyrazol-5-yl]phenoxy}ethyl)aminehydrochloride

[2243] amorphous powder

[2244] MS (ESI+) : m/z 356 (M+H)

[2245] 1HNMR (200 MHz, DMSOd6): 2.52 (3H, s), 3.14-3.23 (2H, m), 3.77(3H, s), 4.15-4.21 (2H, m), 6.57 (1H, s), 6.95 (4H, d, J =8.9 Hz), 7.17(4H, d, J=8.9 Hz), 8.22 (2H, brs)

[2246] The following compound(s) was(were) obtained in a similar mannerto that of Example 428.

[2247] Example 450

[2248]5-[4-(aminomethyl)phenyl]-1-(4-methoxyphenyl)-1-H-pyrazole-3-carbonitrilehydrochloride

[2249] MASS (ESI+): m/z =304.2 (M+1).

[2250] Example 451

[2251] To a solution of(2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)aminedihydrochloride (126.4 mg) andEt3N (125p1) in CH2Cl2 (2 mg) was addedmethanesulfonyl chloride (34.7p1) under ice bath cooling. The mixturewas stirred at ambient temperature for 1 hour. Additionalmethanesulfonyl chloride (6.9p1) and Et3N (41.6p1) were added and thereaction mixture was stirred at ambient temperature for 30 minutes. Themixture was concentrated in vacuo, and the residue was partitionedbetween AcOEt and 1M HC1. The aqueous layer was reextracted with AcOEt.The combined organic layers were washed with saturated aqueoussodiumbicarbonate solution and saturated aqueous sodium chloridesolution, dried over magnesium sulfate, and concentrated in vacuo. Theresidue was purified by preparative thin layer silica gel chromatographydeveloped by AcOEt/n-hexane=70%. The seaparated silica gel was extractedwith 10% MeOH/CDCl3 and the solvent was evaporated in vacuo. The residuewas crystallized from AcOEt-IPE to giveN-(2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)methane-sulfonamide (48.0 mg) as whitepowder.

[2252] mp. 96-99° C.

[2253] IR (KBr) : 3205, 3140, 1612, 1502 cm−1

[2254] MS (ESI+) m/z 429 (M+H)

[2255] 1H NMR (CDCl3) δ 2.20 (3H, s), 3.03 (3H, s), 3.51-3.60 (2H, m),3.93 (3H, s), 4.07-4.13 (2H, m), 4.75 (1H, t, J=5.8 Hz), 5.15 (1H,brs),5.60 (1H,brs), 6.59 (1H, s), 6.73 (1H, d, J=8.9 Hz), 6.83 (2H, d, J=8.8Hz), 7.17 (2H, d, J=8.8 Hz), 7.55 (1H, dd, J=2.6,8.8 Hz), 8.09 (1H, d,J=2.6 Hz))

[2256] The following compound(s) was(were) obtained in a similar mannerto that of Example 451.

[2257] Example 452

[2258]N-(2-{4-[3-{[(dimethylamino)carbonyl]amino}-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)methane-sulfonamide

[2259] powder : mp. 166-167° C.

[2260] IR (KBr) : 3309, 3188, 3182, 3174, 1657, 1651, 1643, 1568, 1514cm−1

[2261] Mass (ESI+) : 474 (M+H)+

[2262] 200 MHz 1H NMR (CDCl3, d) : 3.02 (3H, s), 3.04 (6H, s), 3.49-3.57(2H,m),3.81 (3H,s),4.07 (2H,t,J=5.OHz),4.84 (1H, t, J=5.5 Hz), 6.78 (2H,d, J=8.9 Hz), 6.85 (2H, d, J=9.0 Hz), 6.85 (1H, s), 7.05 (1H, s), 7.15(2H, d, J=9.0 Hz), 7.18 (2H, d, J=8.9 Hz)

[2263] Example 453

[2264]N-(2-{4-[3-[[(dimethylamino)carbonyl](methyl)amino]-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenoxy)ethyl)-methanesulfonamide

[2265] amorphous

[2266] IR (neat) : 1658, 1649, 1641, 1631, 1620, 1612, 1518, 1502 cm−1

[2267] Mass (ESI+) : 488 (M+H)+

[2268] 200 MHz1HNMR (DMSO-d6, d) : 2.79 (6H, s), 2.94 (3H, s), 3.12 (3H,s), 3.30-3.34 (2H, m), 3.76 (3H, s), 4.02 (2H, t, J=5.4 Hz), 6.26 (1H,s), 6.92 (2H, d, J=8.7 Hz), 6.94 (2H, d, J=8.9 Hz), 7.16 (2H, d, J=8.7Hz), 7.16 (2H, d, J=8.9 Hz), 7.29 (1H, s)

[2269] Example 454

[2270]N-(2-{4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)methanesulfonamide

[2271] white powder : mp. 112-114° C.

[2272] IR (KBr) : 3280, 1612 cm−1

[2273] Mass (ESI+) : 423 (M+H)+

[2274] 200 MHz 1H NMR (DMSO-d6, d) : 2.94 (3H, s), 3.29-3.34 (2H, m),3.87 (3H, s), 4.03 (2H, t, J=5.4 Hz), 6.75 (1H, s), 6.89 (1H, d, J=8.8Hz), 6.96 (2H, d, J=8.7 Hz), 7.20 (2H, d, J=8.7 Hz), 7.29 (1H,brs), 7.67(1H, dd, J=2.7,8.8 Hz), 8.11 (1H, d, J=2.7 Hz)

[2275] Example 455

[2276]N-(2-{4-[3-methoxy-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenoxy)ethyl)methanesulfonamide

[2277] mp. 103-104° C.

[2278] IR (KBr) : 3271, 1612, 1579, 1560, 1520, 1514 cm−1

[2279] Mass (ESI+) : 418 (M+H)+

[2280] 200 MHz 1H NMR (DMSO-d6, d) : 2.94 (3H, s), 3.28-3.33 (2H, m),3.76 (3H, s), 3.83 (3H, s), 3.98-4.05 (2H, m), 6.05 (1H, s), 6.88-6.96(4H, m), 7.09-7.17 (4H, m), 7.27 (1H, s)

[2281] Example 456

[2282]N-(2-{4-[3-methoxy-l-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)ethanesulfonamide

[2283] white powder : mp. 117.8-118.0° C.

[2284] IR (KBr): 3269, 1612, 1552, 1520 cm−1

[2285] Mass (ESI+) : 432 (M+H)+

[2286] 200 MHz 1H NMR (DMSO-d6, d) : 1.18 (3H, t, J=7.3 Hz), 3.04 (2H,q, J=7.3 Hz), 3.26-3.34 (2H, m), 3.75 (3H, s), 3.83 (3H, s), 3.96-4.03(2H, m), 6.05 (1H, s), 6.91 (2H, d, J=8.9 Hz), 6.92 (2H, d, J=9.0 Hz),7.09-7.17 (4H, m), 7.32 (1H, brs)

[2287] Example 457

[2288]N-(2-{4-[3-ethoxy-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]-phenoxy}ethyl)methanesulfonamide

[2289] white powder : mp. 146-147° C.

[2290] IR (KBr): 3130, 1612, 1518 cm−1

[2291] Mass (ESI+) : 432 (M+H)+

[2292] 200 MHz 1H NMR (DMSO-d6, d) : 1.33 (3H, t, J=7.0 Hz), 2.94 (3H,s), 3.27-3.36 (2H, m), 3.75 (3H, s), 3.98-4.05 (2H, m), 4.17 (2H, q,J=7.0 Hz), 6.03 (1H, s), 6.91 (2H, d, J=8.8 Hz), 6.92 (2H, d, J=9.0 Hz),7.12 (2H, d, J=9.0 Hz), 7.14 (2H, d, J=8.8 Hz), 7.29 (1H, t, J=5.8 Hz)

[2293] Example 458

[2294]N-(2-{4-[3-isobutoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)methanesulfonamide

[2295] white powder : mp. 164.3-165.2° C.

[2296] IR (KBr) : 3140, 2952, 2933, 2870, 1614, 1518 cm−1

[2297] Mass (ESI+) : 460 (M+H)+

[2298] 200 MHz 1HNMR (DMSO-d6, d) : 0.97 (6H, d, J=6.8 Hz), 2.03 (1H,m), 2.94 (3H, s), 3.27-3.36 (2H, m), 3.75 (3H, s), 3.90 (2H, d, J=6.6Hz), 3.99-4.05 (2H, m), 6.05 (1H, s), 6.88-6.96 (4H, m), 7.12 (2H, d,J=9.0 Hz), 7.14 (2H, d, J=8.8 Hz), 7.28 (1H, t, J=5.8 Hz)

[2299] Example 459

[2300]N-(2-{4-[3-(2-methoxyethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy)ethyl)methanesulfonamide

[2301] white powder : mp. 94.5-94.7° C.

[2302] IR (KBr) : 3319, 2933, 2891, 1612, 1520 cm−1

[2303] Mass (ESI+) : 462 (M+H)+

[2304] 200 MHz 1HNMR (DMSO-d6, d) : 2.94 (3H, s), 3.29-3.35 (2H, m),3.30 (3H, s), 3.62-3.67 (2H, m), 3.75 (3H, s), 3.98-4.05 (2H, m),4.22-4.27 (2H, m), 6.05 (1H, s), 6.89-6.95 (4H, m), 7.10-7.17 (4H, m),7.28 (1H, s)

[2305] Example 460

[2306]N-(2-{4-[3-(2-ethoxyethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)methanesulfonamide

[2307] white powder: mp. 116.3-116.4° C.

[2308] IR (KBr): 3141, 2873, 1612, 1518 cm−1

[2309] Mass (ESI+) : 476 (M+H)+

[2310] 200 MHz 1H NMR (DMSO-d6, d) : 1.13 (3H, t, J=7.0 Hz), 2.94 (3H,s), 3.28-3.40 (2H, m), 3.49 (2H, q, J=7.0 Hz), 3.66-3.71 (2H, m), 3.75(3H, s), 3.98-4.05 (2H, m), 4.21-4.26 (2H, m), 6.06 (1H, s), 6.89-6.95(4H, m), 7.09-7.17 (4H, m), 7.29 (1H, brs)

[2311] Example 461

[2312]N-(2-{4-[3-methoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)methanesulfonamide

[2313] mp. 116-117.5° C.

[2314] IR (KBr) 3126, 1614, 1520, 1500 cm−1

[2315] MS (ESI+) : m/z 419 (M+H)+

[2316] 200 MHz 1H NMR (DMSO-d6, d): 2.94 (3H, s), 3.28-3.36 (2H, m),3.85 (3H, s), 4.00-4.06 (2H, m) , 6.11 (1H, s) , 6.85 (1H, d, J=8.9 Hz),6.94 (2H, d, J=8.8 Hz), 7.18 (2H, d, J=8.8 Hz), 7.29 (1H, s), 7.60 (1H,dd, J=2.6,8.9 Hz), 8.00 (1H, d, J=2.6 Hz))

[2317] Example 462

[2318]N-(2-{4-[3-ethoxy-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)methanesulfonamide

[2319] white powder : mp. 122.0-122.6° C.

[2320] IR (KBr) : 3242, 1614, 1518, 1502 cm−1

[2321] MS (ESI+) : m/z 433 (M+H)+

[2322] 200 MHz 1H NMR (DMSO-d6, d) : 1.33 (3H, t, J=7.0 Hz), 2.94 (3H,s),3.29-3.35 (2H,m),3.84 (3H,s), 4.00-4.06 (2H,m), 4.19 (2H, q, J=7.0Hz), 6.10 (1H, s), 6.85 (1H, d, J=8.8 Hz), 6.94 (2H, d, J=8.7 Hz), 7.18(2H, d, J=8.7 Hz), 7.29 (1H, brs), 7.59 (1H, dd, J=2.7, 8.8 Hz), 7.99(1H, d, J=2.7 Hz)

[2323] Example 463

[2324]N-(2-{4-[1-(4-methoxyphenyl)-4-methyl-3-(trifluoro-methyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)methane-sulfonamide

[2325] MASS (ESI+): m/z =492.1 (M+Na).

[2326] 1HNMR (400 MHz, CDCl3) : 2.15 (3H, s), 3.03 (3H, s), 3.53-3.57(2H, m), 3.79 (3H, s), 4.11 (2H, t, J =5.0 Hz), 4.78 (1H, t, J =6.0 Hz),6.81 (2H, d, J =9.0 Hz), 6.86 (2H, d, J =8.8 Hz), 7.08 (2H, d, J =8.8Hz), 7.13 (2H, d, J =9.0 Hz)

[2327] Example 464

[2328]N-[2-(4-{3-(difluoromethyl)-1-[4-(methylthio)phenyl]1-H-pyrazol-5-yl)phenoxy)ethyl]methanesulfonamide

[2329] mp: 122.7-122.8° C.

[2330] MASS (ESI+): m/z =476.1 (M+Na).

[2331] 1HNMR (400 MHz, CDCl3): 2.49 (3H, s), 3.03 (3H, s), 3.55 (2H, dt,J =4.9 , 6 Hz), 4.1 (2H, t, J =4.9 Hz), 4.8 (1H, t, J =6 Hz), 6.66 (1H,s), 6.76 (1H, t, J =55 Hz), 6.83 (2H, d, J =8.8 Hz), 7.16 (2H, d, J =8.8Hz), 7.22 (4H, s).

[2332] Example 465

[2333]N-{4-[1-(6-methoxy-3-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzyl}methanesulfonamide

[2334] Crystal. mp: 125-126° C.

[2335] MASS (ESI+): 449.0 (M+Na).

[2336] 1HNMR (400 MHz, CDCl3): 2.91 (3H, s), 3.94 (3H, s), 4.34 (2H, d,J =6.2 Hz), 4.74 (1H, t, J =6.2 Hz), 6.74 1H, s), 6.77 (1H, d, J=8.8Hz), 7.24 (2H, d, J=8.3 Hz), 7.35 (2H, d, J =8.3 Hz), 7.58 (1H, dd, J=2.7 ,8.8 Hz), 8.03 (1H, d, J 2.7 Hz)

[2337] Example 466

[2338]N-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]benzyl}methanesulfonamide

[2339] mp: 125.7-126.1° C.

[2340] MASS (ESI+): m/z =431.0 (M+Na).

[2341] 1HNMR (400 MHz, CDCl3): 2.92 (3H, s), 3.94 (3H, s), 4.33 (2H, d,J =6.1 Hz), 4.73 (1H, b.s), 6.74 (1H, s), 6.77 (1H, t, J =55 Hz), 7.24(2H, d, J =8.8 Hz), 7.25 (1H, d, J =7.9 Hz), 7.34 (2H, d, J =7.9 Hz),7.55 (1H, dd, J =2.3 ,8.8 Hz), 8.03 (1H, d, J =2.3 Hz) )

[2342] Example 467

[2343]N-(2-{4-[3-cyclopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy)ethyl)methanesulfonamide

[2344] mp.95-97° C.

[2345] MS (ESI+) : m/z 429 (M+H)

[2346] 1HNMR (200 MHz, ): 0.70-0.78 (2H, m) , 0.87-0.98 (2H, m),1.87-1.99 (1H, m), 2.94 (3H, s), 3.20-3.52 (2H, m), 3.85 (3H, s),3.99-4.05 (2H, m), 6.30 (1H, s), 6.85 (1H, d, J =8.8 Hz), 6.93 (2H, d,J=8.7 Hz), 7.15 (2H, d, J=8.7 Hz), 7.27 (1H, brs), 7.59 (1H, dd, J=2.7,8.8 Hz), 8.00 (1H, d, J =2.7 Hz)

[2347] Example 468

[2348]N-(2-{4-[1-(4-methoxyphenyl)-3-(l-piperidinylcarbonyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)methanesulfonamide

[2349] mp.149.1-150.3° C.

[2350] Mass (ESI+) : 499 (M+H)

[2351] 1HNMR (200 MHz, DMSOd6): 1.43-1.74 (6H, m), 2.94 (3H, s),3.25-3.39 (2H, m), 3.52-3.70 (2H, m), 3.77-3.92 2H, m), 3.78 (3H, s),3.99-4.06 (2H, m), 6.78 (1H, s), 6.93 (2H, d, J =8.9 Hz), 6.98 (2H, d, J=8.9 Hz), 7.18 (2H, d, J =8.9 Hz), 7.23 (2H, d, J =8.9 Hz), 7.27 (1H,brs)

[2352] Example 469

[2353]N-(2-{4-[1-(6-methoxy-3-pyridinyl)-3-(1-piperidinyl-carbonyl)-1H-pyrazol-5-yl]phenoxy}ethyl)methane-sulfonamide

[2354] mp.158.8-159.1° C.

[2355] Mass (ESI+) : m/z 500 (M+H)

[2356] 1HNMR (200 MHz, DMSOd6): 1.43-1.74 (6H, m), 2.94 (3H, s),3.22-3.40 (2H, m), 3.52-3.69 (2H, m), 3.75-3.91 (2H, m), 3.87 (3H, s),4.00-4.07 (2H, m), 6.82 (1H, s), 6.90 (1H, d, J =8.8 Hz), 6.96 (2H, d, J8.8 Hz), 7.22 (2H, d, J =8.8 Hz), 7.28 (1H, brs), 7.68 (1H, dd, J =2.7,8.8 Hz), 8.14 (1H, d, J =2.7 Hz)

[2357] Example 470

[2358]N-ethyl-1-(4-methoxyphenyl)-N-methyl-5-(4-{2-[(methyl-sulfonyl)amino]ethoxy}phenyl)-1H-pyrazole-3-carboxamide

[2359] mp.106.0-106.3° C.

[2360] Mass (ESI+) : m/z 473 (M+H)

[2361] 1HNMR (200 MHz, DMSOd6) : 1.08-1.22 (3H, m) , 2.94 (3H, s), 2.97,3.29 (3H, s), 3.28-3.35 (2H, m), 3.42-3.53, 3.67-3.79 (2H, m), 3.78 (3H,s), 3.99-4.06 (2H, m), 6.79, 6.81 (1H, s), 6.93 (2H, d, J =8.9 Hz), 6.98(2H, d, J =9 Hz), 7.15-7.26 (4H, m), 7.28 (1H, brs)

[2362] Example 471

[2363]N-ethyl-1-(6-methoxy-3-pyridinyl)-N-methyl-5-(4-{2-[(methylsulfonyl)amino]ethoxy}phenyl)-1H-pyrazole-3-carboxamide

[2364] mp.110-111° C.

[2365] Mass (ESI+) : m/z 474 (M+H)

[2366] 1HNMR (200 MHz, DMSOd6) : 1.09-1.23 (3H, m), 2.94 (3H, s), 2.98,3.28 (3H, s), 3.28-3.36 (2H, m), 3.42-3.55, 3.66-3.78 (2H, m), 3.87 (3H,s), 4.01-4.07 (2H, m), 6.83, 6.85 (1H, s), 6.90 (1H, d, J =9.0 Hz), 6.96(2H, d, J=8.7 Hz), 7.22 (2H, d, J =8.7 Hz) ) , 7.28 (1H, brs), 7.61-7.75(1H, m), 8.14-8.16 (1H, m)

[2367] Example 472

[2368]N-(2-{4-[3-isobutyryl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxylethyl)methanesulfonamide

[2369] mp. 155.6-155.8° C.

[2370] MS (ESI+) : m/z 459 (M+H)

[2371] 1HNMR (200 MHz, DMSOd6): 1.16 (6H, d, J =6.9 Hz), 2.94 3H, s),3.25-3.40 (2H, m), 3.68 (1H, m), 3.88 (3H, s), 4.01-4.07 (2H, m), 6.93(1H, d, J =8.7 Hz), 6.96 (2H, d, J =8.7 Hz), 7.02 (1H, s) , 7.23 (2H, d,J =8.7 Hz), 7.28 (1H, brs), 7.74 (1H, dd, J =2.7 ,8.7 Hz), 8.18 (1H, d,J =2.7 Hz)

[2372] Example 473

[2373]N-(2-{4-[3-(cyclopentyloxy)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxylethyl)methanesulfonamide

[2374] oil

[2375] MS (ESI+) : m/z 473 (M+H)

[2376] 1HNMR (200 MHz, DMSOd6) : 1.51-2.00 (8H, m), 2.94 (3H, s),3.24-3.39 (2H, m), 3.84 (3H, s), 4-4.06 (2H, m), 4.98 (1H, m), 6.07 (1H,s), 6.84 (1H, d, J =8.8 Hz), 6.94 (2H, d, J =8.8 Hz), 7.18 (2H, d, J=8.8 Hz), 7.28 (1H, brs), 7.58 (1H, dd, J =2.7 ,8.8 Hz), 7.99 (1H, d, J=2.7 Hz)

[2377] Example 474

[2378]N-(2-{4-[1-(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1-H-pyrazol-5-yl]phenoxy}ethyl)methanesulfonamide

[2379] mp.131.3-131.4° C.

[2380] MS (ESI+) : m/z 486 (M+H)

[2381] 1HNMR (200 MHz, DMSOd6) : 2.94 (3H, s), 3.25-3.39 (2H, m), 3.76(3H, s), 3.99-4.05 (2H, m), 4.81 (1H, d, J =9.0 Hz), 4.90 (1H, d, J =9.0Hz), 6.22 (1H, s), 6.90-6.98 (4H, m), 7.11-7.18 (4H, m), 7.28 (1H, brs)

[2382] Example 475

[2383]N-(2-{4-[3-(2,2-difluoroethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)methanesulfonamide

[2384] mp. 145.0-145.1° C.

[2385] MS (ESI+) : m/z 468 (M+H)

[2386] 1HNMR (200 MHz, DMSOd6): 2.93 (3H, s), 3.28-3.34 (2H, m), 3.76(3H, s), 3.99-4.05 (2H, m), 4.44 (2H, dt, J =3.5,14.9 Hz), 6.15 (1H, s),6.41 (1H, tt, J=3.5, 54.6 Hz), 6.92 (2H, d, J =9.0 Hz), 6.93 (2H, d, J=9.0 Hz), 7.11-7.18 (4H, m), 7.27 (1H, brs)

[2387] Example 476

[2388]N-(2-{4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoro-ethoxy)-1-H-pyrazol-5-yl]phenoxy}ethyl)methane-sulfonamide

[2389] oil

[2390] MS (ESI+) : m/z 487 (M+H)

[2391] 1HNMR (200 MHz, DMSOd6): 2.94 (3H, s), 3.29-3.35 (2H, m), 3.85(3H, s), 4.00-4.06 (2H, m), 4.83 (1H, d, J =9.0 Hz), 4.92 (1H, d, J =9.0Hz), 6.28 (1H, s), 6.87 1H, d, J =8.8 Hz), 6.95 (2H, d, J =8.8 Hz), 7.19(2H, d, J=8.8 Hz), 7.28 (1H, brs), 7.61 (1H, dd, J=2.7 ,8.9 Hz), 8.03(1H, d, J =2.7 Hz)

[2392] Example 477

[2393]N-(2-{4-[3-(2,2-difluoroethoxy)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)methane-sulfonamide

[2394] solid

[2395] MS (ESI+) : m/z 469 (M+H)

[2396] 1HNMR (200 MHz, CDCl3): 3.03 (3H, s), 3.51-3.60 (2H, m), 3.92(3H, s), 4.07-4.13 (2H, m), 4.46 (2H, dt, J =4.2 ,13.4 Hz), 4.76 (1H, t,J=6 Hz), 5.95 (1H, s), 6.17 1H, tt, J =4.2, 55.4 Hz), 6.72 (1H, d, J=8.8 Hz) ) , 6.83 (2H, d, J =8.8 Hz), 7.15 (2H, d, J =8.8 Hz), 7.49 (1H,dd, J =2.8 ,8.8 Hz), 8.01 (1H, d, J =2.8 Hz)

[2397] Example 478

[2398]N-(2-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy)ethyl)-2-hydroxyethanesulfonamide

[2399] mp.139.1-139.4° C.

[2400] MS (ESI+) : m/z 452 (M+H)

[2401] 1HNMR (200 MHz, DMSOd6) : 3.18-3.35 (4H, m), 3.69-3.77 (2H, m),3.78 (3H, s), 3.97-4.04 (2H, m), 4.90 (1H, t, J =5.6 Hz), 6.69 (1H, s),6.90-7.01 (4H, m), 7.14-7.26 (5H, m)

[2402] Example 479

[2403]N-(2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)methanesulfonamide

[2404] oil

[2405] Mass (ESI+) : m/z 439 (M+H)

[2406] 1HNMR (200 MHz, CDC13): 3.03 (3H, s), 3.51-3.60 (2H, m), 3.94(3H, s), 4.08-4.14 (2H, m), 4.75 (1H, t, J =5.6 Hz), 6.68 (1H, s), 6.75(1H, d, J =8.9 Hz), 6.76 (1H, t, J =55 Hz), 6.85 (2H, d, J =8.8 Hz),7.17 (2H, d, J =8.8 Hz), 7.53 (1H, dd, J =2.7 ,8.9 Hz), 8.08 (1H, d, J=2.7 Hz)

[2407] Example 480

[2408]N-{4-[1-(4-methoxyphenyl)-3-(1-piperidinylcarbonyl)-1H-pyrazol-5-yl]benzyllmethanesulfonamide

[2409] mp.179.3-179.6° C.

[2410] MS (ESI+) : m/z 469 (M+H)

[2411] 1HNMR (200 MHz, DMSOd6): 1.42-1.72 (6H, m), 2.85 (3H, s), 3.52-3.69 (2H, m), 3.75-3.92 (2H, m), 3.78 (3H, s), 4.15 (2H, s), 6.85 (1H,s), 6.98 (2H, d, J =9 Hz), 7.21-7.35 (6H, m), 7.58 (1H, brs)

[2412] Example 481

[2413]N-ethyl-1-(4-methoxyphenyl)-N-methyl-5-(4-{[(methyl-sulfonyl)amino]methyl}phenyl)-1H-pyrazole-3-carboxamide

[2414] mp.149.8-150.8° C.

[2415] MS (ESI+) : m/z 443 (M+H)

[2416] 1HNMR (200 MHz, DMSOd6) : 1.09-1.21 (3H, m), 2.86 (3H, s), 2.98,3.29 (3H, s), 3.40-3.78 (2H, m), 3.78 (3H, s), 4.13-4.17 (2H, m), 6.86,6.88 (1H, s), 6.98 (2H, d, J =9 Hz), 7.21-7.35 (6H, m), 7.58 (1H, brs)

[2417] Example 482

[2418]N-{4-[3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-benzyl}methanesulfonamide

[2419] mp.130.9-131.0° C.

[2420] MS (ESI+) : m/z 400 (M+H)

[2421] 1HNMR (200 MHz, DMSOd6): 1.27 (6H, d, J =6.9 Hz), 2.84 (3H, s),2.96 (1H, m), 3.76 (3H, s), 4.14 (2H, s), 6.47 (1H, s), 6.93 (2H, d, J=8.9 Hz), 7.11-7.21 (4H, m), 7.30 (2H, d, J =8.2 Hz), 7.56 (1H, brs)

[2422] Example 483

[2423]N-{4-[3-isobutyryl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}methanesulfonamide

[2424] mp.155.8-155.9° C.

[2425] MS (ESI+) : m/z 428 (M+H)

[2426] 1HNMR (200 MHz, ) : 1.16 (6H, d, J =6.9 Hz), 2.86 (3H, s), 3.68(1H, m), 3.79 (3H, s), 4.15 (2H, s), 7.00 (2H, d, J =8.9 Hz), 7.06 (1H,s), 7.22-7.35 (6H, m), 7.58 (1H, s)

[2427] Example 484

[2428] N-{4-[1-(6-methoxy-3-pyridinyl)-3-(1-piperidinyl-carbonyl)-1H-pyrazol-5-yl]benzyl)methanesulfonamide

[2429] mp.182.6-182.9° C.

[2430] MS (ESI+) : m/z 470 (M+H)

[2431] 1HNMR (200 MHz, DMSOd6): 1.42-1.72 (6H, m), 2.86 (3H, s),3.53-3.69 (2H, m), 3.75-3.9 (2H, m), 3.87 (3H, s), 4.16 (2H, s) , 6.89(1H, s), 6.90 (1H, d, J =8.8 Hz), 7.28 (2H, d, J =8.4 Hz), 7.36 (2H, d,J =8.4 Hz) ) , 7.59 1H, s), 7.70 (1H, dd, J =2.7 ,8.8 Hz), 8.14 (1H, d,J =2.7 Hz)

[2432] Example 485

[2433]N-ethyl-1-(6-methoxy-3-pyridinyl)-N-methyl-5-(4-{[(methylsulfonyl)amino]methyl}phenyl)-1H-pyrazole-3-carboxamide

[2434] white powder

[2435] MS (ESI+) : m/z 444 (M+H)

[2436] 1HNMR (200 MHz, DMSOd6): 1.09-1.23 (3H, m), 2.86 (3H, s), 2.98,3.29 (3H, s), 3.49, 3.72 (2H, q, J =7.1 Hz), 3.87 (3H, s), 4.16 (2H, s),6.88-6.93 (2H, m), 7.28 (2H, d, J =8.3 Hz), 7.36 (2H, d, J =8.3 Hz),7.56 (1H, brs), 7.65-7.74 (1H, m), 8.13-8.14 (1H, m)

[2437] Example 486

[2438]N-{4-[3-isopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]benzyl}methanesulfonamide

[2439] oil

[2440] MS (ESI+) : m/z 401 (M+H)

[2441] 1HNMR (200 MHz, CDCl3) : 1.34 (6H, d, J=6.9 Hz), 2.86 (3H, s),3.03 (1H, m) , 3.90 (3H, s), 4.28 (2H, d, J =6.1 Hz), 5.19 (1H, t, J=6.1 Hz), 6.34 (1H, s), 6.72 (1H, d, J =8.8 Hz), 7.21 (2H, d, J=8.2 Hz),7.29 (2H, d, J=8.2 Hz), 7.56 (1H, dd, J =2.7 ,8.8 Hz), 7.98 (1H, d, J=2.7 Hz)

[2442] Example 487

[2443]N-{4-[3-isobutyryl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]benzyl}methanesulfonamide

[2444] mp.160.8-161.2° C.

[2445] MS (ESI+) : m/z 429 (M+H)

[2446] 1HNMR (200 MHz, DMSOd6) : 1.16 (6H, d, J =6.8 Hz), 2.86 3H, s),3.68 (1H, m), 3.88 (3H, s), 4.16 (2H, d, J =5.5 Hz), 6.93 (1H, d, J =8.8Hz), 7.09 (1H, s), 7.29 (2H, d, J =8.3 Hz) ) , 7.36 (2H, d, J =8.3 Hz),7.59 (1H, t, J =5.5 Hz), 7.76 (1H, dd, J =2.8 ,8.8 Hz), 8.18 (1H, d, J=2.7 Hz)

[2447] Example 488

[2448]N-{4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}methanesulfonamide

[2449] mp.94.0-94.3° C.

[2450] MS (ESI+) : m/z 388 (M+H)

[2451] 1HNMR (200 MHz, DMSOd6): 2.85 (3H, s), 3.76 (3H, s), 3.84 (3H,s), 4.14 (2H, s), 6.12 (1H, s), 6.92 (2H, d, J =8.9 Hz), 7.14 (2H, d, J=8.9 Hz), 7.20 (2H, d, J =8.2 Hz), 7.30 (2H, d, J =8.2 Hz), 7.57 (1H, s)

[2452] Example 489

[2453]N-{4-[3-isopropoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}methanesulfonamide

[2454] amorphous

[2455] MS (ESI+) : m/z 416 (M+H)

[2456] 1HNMR (200 MHz, DMSOd6) : 1.32 (6H, d, J =6.1 Hz), 2.85 (3H, s),3.75 (3H, s), 4.14 (2H, s), 4.77 (1H, m), 6.07 (1H, s), 6.91 (2H, d,J=8.9 Hz), 7.13 (2H, d, J=8.9 Hz), 7.19 (2H, d, J =8.2 Hz), 7.30 (2H, d,J=8.2 Hz), 7.57 (1H, brs)

[2457] Example 490

[2458]N-{4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoro-ethoxy)-1-H-pyrazol-5-yl]benzyl}methanesulfonamide

[2459] mp.130-131° C.

[2460] Mass (ESI+) : 457 (M+H)

[2461] 1HNMR (200 MHz, CDC13): 2.92 (3H, s), 3.93 (3H, s), 4.33 (2H, d,J =6.0 Hz), 4.54-4.71 (1H, m), 4.62 (1H, d, J =8.4 Hz), 4.70 (1H, d, J=8.4 Hz), 6.04 (1H, s), 6.73 (1H, d, J =8.8 Hz), 7.22 (2H, d, J =8.3Hz), 7.33 (2H, d, J =8.3 Hz), 7.52 (1H, dd, J =2.7 ,8.8 Hz), 7.95 (1H,d, J =2.7 Hz)

[2462] Example 491

[2463]N-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}methanesulfonamide

[2464] mp.68.3-69.3° C.

[2465] Mass (ESI+) : 392 (M+H)

[2466] 1HNMR (200 MHz, DMSOd6): 2.85 (3H, s), 3.77 (3H, s), 4.14 2H, s),6.76 (1H, s), 6.96 (2H, d, J =8.9 Hz), 7.17-7.24 (4H, m), 7.32 (2H, d, J=8.2 Hz), 7.58 (1H, s)

[2467] Example 492

[2468]N-{4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]benzyl}methanesulfonamide

[2469] oil

[2470] Mass (ESI+) : 393 (M+H)

[2471] 1HNMR (200 MHz, DMSOd6) : 2.86 (3H, s), 3.86 (3H, s), 4.16 (2H,s), 6.82 (1H, s), 6.89 (1H, d, J =8.8 Hz), 7.26 (2H, d, J =8.3 Hz), 7.35(2H, d, J =8.3 Hz), 7.59 (1H, brs) , 7.69 (1H, dd, J =2.7 ,8.8 Hz)) ,8.1 (1H, d, J =2.7 Hz)

[2472] Example 493

[2473]N-(2-{4-[1-(4-methoxyphenyl)-3-(methylthio)-1H-pyrazol-5-yl]phenoxy}ethyl)methanesulfonamide

[2474] mp. 165.0-166.0° C.

[2475] MS (ESI+) : m/z 434 (M+H)

[2476] 1HNMR (200 MHz, DMSOd6) : 2.51 (3H, s), 2.94 (3H, s), 3.27-3.36(2H, m), 3.77 (3H, s), 3.99-4.05 (2H, m), 6.56 1H, s), 6.92 (2H, d,J=8.8 Hz), 6.95 (2H, d, J=8.9 Hz), 7.15 (2H, d, J =8.8 Hz), 7.17 (2H, d,J =8.9 Hz), 7.27 1H, t, J =5.8 Hz)

[2477] Example 494

[2478]N-(2-{4-[1-(6-methoxy-3-pyridinyl)-3-(trifluoromethyl)-1-H-pyrazol-5-yl]phenyl}ethyl)benzenesulfonamide

[2479] amorphous powder

[2480] Mass (ESI+) : 503 (M+H)+

[2481] 200 MHz 1HNMR (DMSO-d6, d) : 2.64-2.72 (2H,m), 2.91-3.02 (2H, m),3.88 (3H, s), 6.91 (1H, d, J=9.0 Hz), 7.03-7.21 (5H, m), 7.56-7.80 (7H,m), 8.18 (1H, d, J=2.6 Hz))

[2482] Example 495

[2483]N-methoxy-1-(4-methoxyphenyl)-N-methyl-5-(4-{2-[(methylsulfonyl)amino]ethyl}phenyl)-1H-pyrazole-3-carboxamide

[2484] oil

[2485] Mass (ESI+) : m/z 459 (M+H)

[2486] 1HNMR (200 MHz, CDCl3): 2.84-2.91 (2H, m) , 2.87 (3H, s),3.35-3.46 (2H, m), 3.51 (3H, s), 3.83 (3H, s), 3.85 (3H, s), 4.26 (1H,t, J=6.2 Hz), 6.86 (2H, d, J =9.0 Hz), 6.97 (1H, s), 7.12-7.29 (6H, m)

[2487] Example 496

[2488]N-methoxy-1-(6-methoxy-3-pyridinyl)-N-methyl-5-(4-{2-[(methylsulfonyl)amino]ethyl}phenyl)-1H-pyrazole-3-carboxamide

[2489] oil

[2490] Mass (ESI+) : m/z 460 (M+H)

[2491] 1HNMR (200 MHz, CDCl3) : 2.80 2.93 (2H, m) , 2.88 (3H, s),3.36-3.47 (2H, m), 3.50 (3H, s), 3.85 (3H, s), 3.94 (3H, s), 4.28 (1H,t, J =6.2 Hz), 6.75 (1H, d, J=8.8 Hz), 6.98 (1H, s), 7.20 (4H, s), 7.56(1H, dd, J =2.7 ,8.8 Hz), 8.10 (1H, d, J =2.7 Hz)

[2492] Example 497

[2493] Trimethylsilyl isocyanate (73.8 νl) was adddedto a solution of(2-14-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)aminedihydrochloride (115.4 mg) and Et3N (114 μl) and the mixture was stirredat ambient temperature for 1.5 hours. The mixture was concentrated invacuo and the residue was partitioned between AcOEt and 1M HCl. Theaqueous layer was reextracted with AcOEt. The combined organic layerswere washedwith saturated aqueous sodium bicarbonate solution andsaturated aqueous sodium chloride solution, dried overmagnesium sulfate,and concentrated in vacuo. The residue was purified by preparative thinlayer silica gel chromatography developed by 10% MeOH/CHCl3. Theseaparated silica gel was extracted with 10% MeOH/CHCl3 and the solventwas evaporated in vacuo. The residue was crystallized from AcOEt-IPE togiveN-(2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)urea(40.1 mg) as a white powder.

[2494] white powder : mp. 94-98° C.

[2495] IR (KBr) : 3435, 3388, 3344, 3333, 1657, 1631, 1610, 1577, 1572,1562, 1552, 1502 cm−1

[2496] 1H NMR (DMSO-d6) δ 2.10 (3H, s), 3.28-3.27 (2H, m), 3.86 (3H, s),3.91-3.97 (2H, m), 5.15 (1H, brs), 5.53 (2H, s), 5.62 (1H, brs), 6.16(1H, t, J=5.5 Hz), 6.84 (1H, s), 6.88 (1H, d, J=8.8 Hz), 6.95 (2H, d,J=8.8 Hz), 7.19 (2H, d, J=8.8 Hz), 7.64 (1H, dd, J=2.7,8.8 Hz), 8.07(1H, d, J=2.7 Hz))

[2497] The following compound(s) was(were) obtained in a similar mannerto that of Example 497.

[2498] Example 498

[2499]N-(2-{4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea

[2500] mp. 108-111° C.

[2501] IR (KBr) : 3388, 3342, 1657, 1631, 1612, 1593, 1577, 1562, 1522cm−1

[2502] Mass (ESI+) : 383 (M+H)+

[2503] 200 MHz 1H NMR (CDC13, d) : 3.54-3.62 (2H, m), 3.79 (3H, s), 3.96(3H,s),3.98-4.04 (2H,m),4.44 (2H, s),5.03 (1H,t,J=5.5 Hz), 5.88 (1H, s),6.78 (2H, d, J=8.8 Hz), 6.82 (2H, d, J=8.9 Hz), 7.12 (2H, d, J=8.8 Hz),7.16 (2H, d, J=8.9 Hz))

[2504] Example 499

[2505]N-(2-{4-[3-ethoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy)ethyl)urea

[2506] white powder : mp. 154.2-154.4° C.

[2507] IR (KBr) : 3398, 3332, 1658, 1631, 1612, 1566, 1518 cm−1

[2508] Mass (ESI+) : 397 (M+H)+

[2509] 200 MHz 1H NMR (DMSO-d6, d) : 1.33 (3H, t, J=7.0 Hz), 3.27-3.34(2H, m), 3.75 (3H, s), 3.89-3.96 (2H, m), 4.17 (2H, q, J=7.0 Hz), 5.53(2H, s), 6.03 (1H, s), 6.15 (1H, t, J=5.6 Hz), 6.90 (2H, d, J=8.9 Hz),6.92 (2H, d, J=9.0 Hz), 7.10-7.15 (4H, m)

[2510] Example 500

[2511] Imidazole (680 mg) and t-butyldimethylsilyl chloride (903 mg) wasadded successively to a solution of ethyl5-[4-{2-(hydroxy)ethoxy}phenyl]-1-(4-methoxyphenyl)-1-H-pyrazole-3-carboxylate(1.91 g) in DMF (15 mg) under cooling in an ice bath. After stirring atambient temperature for 2 hours, the mixture was partitioned betweenAcOEt and H2O. The oreganic layer was washed with H2O, saturated aqueoussodium chloride solution, dried over MgSO4, concentrated in vacuo. Theresidual crystals were collected and washed with n-hexane to give ethyl5-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-phenyl]-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate(2.34 g).

[2512] powder

[2513] mp. 86-87° C.

[2514] MS (ESI+) : m/z 497 (M+H)

[2515] 1HNMR (CDCl3) δ 0.09 (6H, s), 0.90 (9H, s), 1.42 (3H, t, J=7.1Hz), 3.82 (3H, s), 3.94-3.97 (2H, m), 4.01-4.04 (2H, m), 4.44 (2H, q,J=7.1 Hz), 6.83 (2H, d, J=8.7 Hz), 6.85 (2H, d, J=8.9 Hz), 6.96 (1H, s),7.11 (2H, d, J=8.7 Hz), 7.24 (2H, d, J=8.9 Hz)

[2516] Example 501

[2517] A solution of ethyl 5- [4- (2-{ [tert-butyl (dimethyl)silyl]-oxy}ethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate(0.3 g) in THF (3 mg) was added dropwise to a 1M solution ofmethylmagnesium bromide (3 mg) at ambient temperature. The reactionmixture was stirred at ambient temperature for 1 hour, then was pouredinto a mixture of crushed ice and saturated aqueous ammonium chloridesolution. The mixture was extracted with AcOEt. The oreganic layer waswashed with saturated aqueous sodium bicarbonate solution and saturatedaqueous sodium chloride solution, dried over magnesium sulfate, andconcentrated in vacuo to give2-[5-[4-(2-l[tert-butyl(dimethyl)silyl]oxy}-ethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-2-propanol(0.27 g) as an oil.

[2518] oil

[2519] MS (ESI+) : m/z 483 (M+H)

[2520] 1H NMR (CDCl3 δ0.09 (6H, s), 0.90 (9H, s), 1.65 (6H, s), 3.81(3H, s), 3.94-3.97 (2H, m), 4.01-4.04 (2H, m), 6.35 (1H, s), 6.82 (2H,d, J=8.8 Hz), 6.85 (2H, d, J=8.9 Hz), 7.12 (2H, d, J=8.8 Hz), 7.21 (2H,d, J=8.9 Hz))

[2521] The following compound(s) was(were) obtained in a similar mannerto that of Example 501.

[2522] Example 502

[2523]N-(2-{4-[3-(1-hydroxy-1-methylethyl)-1-(4-methoxy-phenyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)urea

[2524] white powder : mp. 147-152° C.

[2525] IR (KBr) : 3333, 3271, 2976, 1676, 1664, 1658, 1612, 1547, 1537,1516, 1502 cm−1

[2526] MS (ESI+) : m/z 411 (M+H)

[2527] 1H NMR (DMSO-d6) δ 1.48 (6H, s), 3.22-3.40 (2H, m), 3.76 (3H, s),3.90-3.96 (2H, m), 4.98 (1H, s), 5.52 (2H, s), 6.14 (1H, t, J=5.6 Hz),6.49 (1H, s), 6.90 (2H, d, J=8.7 Hz), 6.94 (2H, d, J=8.8 Hz), 7.12 (2H,d, J=8.7 Hz), 7.15 (2H, d, J=8.8 Hz))

[2528] Example 503

[2529] tert-butyl{4-[3-(1-hydroxy-1-methylethyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}carbamate

[2530] powder

[2531] MS (ESI+) : m/z 438 (M+H)

[2532] 1HNMR (200 MHz, DMSOd6): 1.39 (9H, s), 1.49 (6H, s), 3.76 (3H,s), 4.11 (2H, d, J =6.1 Hz), 5.01 (1H, s), 6.54 (1H, s), 6.94 (2H, d, J=8.9 Hz), 7.15 (2H, d, J =8.9 Hz), 7.17 (4H, brs), 7.4 (1H, t, J =6.1Hz)

[2533] Example 504

[2534] tert-butyl{4-[3-(1-hydroxy-1-methylethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]benzyl}-carbamate

[2535] powder

[2536] MS (ESI+) : m/z 439 (M+H)

[2537] 1HNMR (200 MHz, DMSOd6) 1.39 (9H, s) , 1.49 (6H, s), 3.85 (3H,s), 4.12 (2H, d, J =6.1 Hz), 5.05 (1H, s), 6.59 (1H, s), 6.86 (1H, d, J=8.8 Hz), 7.20 (4H, s), 7.40 (1H, t, J =6.1 Hz), 7.62 (1H, dd, J =2.7,8.8 Hz), 8.00 (1H, d, J =2.7 Hz)

[2538] Example 505

[2539] A solution of2-[5-[4-(2-{[tert-butyl(dimethyl)silyl]-oxylethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-2-propanol(180 mg) in DMF (2 mg) was added dropwise to a suspension of sodiumhydride 60% dispersion in mineral oil (17 mg) in DMF (1 ml) undercooling in an ice bath. After 10 minutes, iodemethane (63.5 mg) wasadded and the reaction mixture was stirred at same temperature for 1hour and at ambient temperature for 1 hour. Additional iodomethane wasadded until all starting material was consumed. The reaction wasquenched by adding saturated ammonium chloride. The mixture wasextracted with ethyl acetate. The organic layer was washed with H2O andsaturated aqueous sodium chloride solution, dried over magnesiumsulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography eluted with AcOEt/n-hexane, which polarity wasgradually changed from 20% to 80%, to give5-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)phenyl]-3-(1-methoxy-1-methylethyl)-1-(4-methoxyphenyl)-1H-pyrazole(32.2 mg) as an oil.

[2540] Mass (ESI+) : 497 (M+H)

[2541] 1H NMR (CDCl3) δ 0.09 (6H, s), 0.90 (9H, s), 1.58 (3H, s), 1.63(3H, s), 3.22 (3H, s), 3.81 (3H, s), 3.93-4.04 (4H, m), 6.42 (1H, s),6.82 (2H, d, J=8.8 Hz), 6.84 (2H, d, J=9.0 Hz), 7.13 (2H, d, J=8.8 Hz),7.22 (2H, d, J=9.0 Hz))

[2542] Example 506

[2543] A 1M solution of tetra-n-butylammonium fluoride in THF (0.24 mg)was added to a solution of 5-[4-(2-{[tert-butyl-(dimethyl)silyl]oxy}ethoxy)phenyl]-3-(1-methoxy-1-methylethyl)-1-(4-methoxyphenyl)-1H-pyrazole(98 mg) in THF(2 mg) under ice bath cooling. The reaction mixture wasstirred at same temperature for 1 hour. The mixture was partitionedbetween ethyl acetate and H2O. The organic layer was washed withsaturated aqueous sodium chloride solution, dried over magnesiumsulfate, and concentrated in vacuo. The residue was purified bypreparative thin layer silica gel chromatography developed by 50%AcOEt/n-hexane. The seaparated silica gel was extracted with 10%MeOH/CHCl3 and the solvent was evaporated in vacuo to give2-{4-[3-(1-methoxy-1-methylethyl)-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenoxy}ethanol(66 mg) as an oil.

[2544] IR (neat) : 3423, 3398, 3371, 2976, 2935, 1647, 1612, 1566, 1549,1512 cm−1

[2545] MS (ESI+) : m/z 383 (M+H)

[2546] 1H NMR (CDCl3 δ 1.60 (3H, s), I.63 (3H, s), 2.03 (1H, t, J=6.1Hz), 3.22 (3H, s), 3.81 (3H, s), 3.91-4.00 (2H, m), 4.05-4.10 (2H,m),6.43 (1H,s), 6.83 (2H,d,J=8.9 Hz), 6.84 (2H, d, J=8.9 Hz), 7.15 (2H, d,J=8.9 Hz), 7.21 (2H, d, J=8.9 Hz))

[2547] Example 507

[2548] A 4M solution of HC1 in dioxane (2 mg) was added to a solution ofethyl 5-(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}-phenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate (300 mg) in CH2Cl2 (3 mg) undercoolingin an ice bath. After stirring at ambient temperature for 1 hour,the reaction mixture was concentrated in vacuo. The residue wasdissolved in CH2Cl2 (3 mg), Et3N (189 mg) and trimethylsilyl isocyanate(108 mg) were added, and the mixture was stirred at ambient temperatureovernight. The stirring was continued for more 4 hours, adding moretrimethylsilyl isocyanate and Et3N to consume all starting material. Themixture was concentrated in vacuo and the residue was partitionedbetween ethyl acetate and 1M HCl. The organic layer was washed withsaturated aqueous sodium bicarbonate solution and saturated aqueoussodium chloride solution, dried over magnesium sulfate, and concentratedin vacuo. The residual crystals were suspended in hot ethyl acetate,cooled with stirring, collected and washed with ethyl acetate to giveethyl5-(4-{2-[(aminocarbonyl)amino]ethoxy}phenyl)-1-(4-methoxyphenyl)-1-H-pyrazole-3-carboxylate(217 mg) as a white powder.

[2549] MS (ESI+) : m/z 425 (M+H) 1H NMR (DMSO-d6) δ1.31 (3H, t, J=7.1Hz), 3.27-3.36 (2H, m), 3.79 (3H, s),3.90-3.96 (2H,m),4.32 (2H,q,J=7.1Hz),5.52 (2H, s), 6.14 (1H, t, J=5.7 Hz), 6.92 (2H, d, J=8.8 Hz), 6.99(2H, d, J=8.8 Hz), 7.01 (1H, s), 7.17 (2H, d, J=8.8 Hz), 7.25 (2H, d,J=8.8 Hz)

[2550] Example 508

[2551] 1M NaOH (5 ml) was added to a solution of ethyl5-(4-{2-[(aminocarbonyl)amino]ethoxy}phenyl)-1-(4-methoxyphenyl)-1-H-pyrazole-3-carboxylate(1.75 g) in THF (15 mg) and MeOH (10 ml). The reaction mixture wasstirred at ambient temperature andconcentrated invacuo. The residue wasdissolved in H2O and acidified by 1M HC1. white precipitates werecollected and washed successively with H2O and IPE to give5-(4-12-[(aminocarbonyl)amino]-ethoxy}phenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylicacid (1.58 g) as a white powder.

[2552] MS (ESI+) : m/z 397 (M+H)

[2553] 1H NMR (DMSO-d6) 6 3.15-3.55 (2H, m), 3.90-3.97 (2H, m), 5.52(2H,s), 6.14 (1H,t, J=5.7 Hz), 6.89-7.03 (5H,m),7.17 (2H, d, J=8.8 Hz),7.24 (2H, d, J=8.9 Hz)

[2554] The following compound(s) was(were) obtained in a similar mannerto that of Example 508.

[2555] Example 509

[2556]5-(4-{[(tert-butoxycarbonyl)amino]methyl}phenyl)-1-(4-methoxyphenyl)-1-H-pyrazole-3-carboxylicacid

[2557] white powder

[2558] MS (ESI+) : m/z 424 (M+H)

[2559] 1HNMR (200 MHz, DMSOd6): 1.38 (9H, s), 3.79 (3H, s), 4.11 (2H, d,J =6.1 Hz), 6.99 (2H, d, J =8.9 Hz), 7.01 (1H, s), 7.20 (4H, brs), 7.25(2H, d, J =8.9 Hz), 7.41 (1H, t, J =6.1 Hz), 12.92 (1H, brs

[2560] Example 510

[2561]5-(4-1[(tert-butoxycarbonyl)amino]methyl}phenyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazole-3-carboxylicacid

[2562] powder

[2563] MS (ESI+) : m/z 425 (M+H)

[2564] 1HNMR (200 MHz, CDCl3): 1.46 (9H, s), 3.95 (3H, s), 4.33 (2H, d,J=5.9 Hz), 4.9 (1H, brs), 6.76 (1H, d, J=8.8 Hz), 7.07 (1H, s), 7.19(2H, d, J =8.4 Hz), 7.27 (2H, d, J =8.4 Hz), 7.58 (1H, dd, J =2.7 ,8.8Hz), 8.11 (1H, d, J =2.7 Hz)

[2565] Example 511

[2566] A mixture of5-(4-{2-[(aminocarbonyl)amino]ethoxy}-phenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylicacid (1.56 g), diphenylphosphoryl azide (1.62 g), and Et3N (597 mg) int-butanol (5 mg) was refluxed for 3 hours. The mixture was concentratedin vacuo, and the residue was partitioned between ethyl acetate and H2O.The combined organic layer was washed twice with 1M HC1. and washed withsaturated aqueous sodium bicarbonate solution and saturated aqueoussodium chloride solution, dried over magnesium sulfate, and concentratedin vacuo. The residue was purified by silica gel column chromatographyelutedwith ethyl acetate to give tert-butyl[5-(4-{2-[(aminocarbonyl)amino]-ethoxy}phenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]carbamate(519 mg) as an amorphous powder.

[2567] MS (ESI+) : m/z 468 (M+H)

[2568] 1HNMR (DMSO-d6) 5 1.46 (9H, s), 3.27-3.36 (2H, m), 3.76 (3H, s),3.90-3.96 (2H, m), 5.52 (2H, s), 6.15 (1H, t, J=5.6 Hz), 6.55 (1H, s),6.90 (2H, d, J=8.9 Hz), 6.93 (2H, d, J=8.9 Hz), 7.13 (4H, d, J=8.9 Hz),9.74 (1H, s)

[2569] Example 512

[2570] A 4M solution of HC1 in dioxane (3 mg) was added to a solution oftert-butyl[5-(4-{2-[(aminocarbonyl)amino]ethoxy}-phenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]carbamate(478 mg) in CH2Cl2 (3 mg) The reaction mixture was stirred at ambienttemperature for 5 hours and concentrated in vacuo. The residue waspartitioned between CDCl3 and saturated aqueous sodium bicarbonatesolution. The aq layer was reextrated with CHCl3. The combined organiclayer was dried over magnesium sulfate, and concentrated in vacuo. Theresidue was purified by silica gel column chromatography eluted withCHC13:MeOH:28% aqueous NH40H=10:1:0.1 to giveN-(2-{4-[3-amino-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea(244.6 mg) as an amorphous powder.

[2571] MS (ESI+) : m/z 368 (M+H)

[2572] IR (neat) : 3400, 3388, 3342, 3330, 1658, 1651, 1643, 1612, 1579,1562, 1554, 1520 cm−1

[2573] 1H NMR (DMSO-d6) δ 3.27-3.37 (2H, m), 3.73 (3H, s), 3.89-3.95(2H, m), 4.83 (2H, s), 5.52 (2H, s), 5.73 (1H, s), 6.15 (1H, t, J=5.5Hz), 6.85-6.92 (4H, m), 7.03-7.12 (4H, m)

[2574] Example 513

[2575] 37% aqueous solution of formaldehyde (0.23 mg) and sodiumcyanoborohydride (53 mg) were added to a solution ofN-(2-{4-[3-amino-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy}ethyl)urea(103.1 mg) in MeOH (2 mg). The reaction mixture was stirred at ambienttemperature for 3 hours. 37% aqueous solution of formaldehyde (0.23 mg)and sodium cyanoborohydride (53 mg) were added to the mixture and thereaction mixture was stirred at ambient temperature for 4 days. Themixture was concentrated in vacuo, and the residue was partitionedbetween ethyl acetate and H2O. The organic layer was washed withsaturated aqueous sodium chloride solution, dried over magnesiumsulfate, and concentrated in vacuo. The residue was purified bypreparative thin layer silica gel chromatography developed by CHC13 :MeOH : 28%aqueous NH40H=100:10:1. The seaparated silica gel wasextracted with same solvent and the solvent was evaporated in vacuo togiveN-(2-{4-[3-(dimethylamino)-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)urea(59.9 mg) as an amorphous powder.

[2576] MS (ESI+) : m/z 396 (M+H)

[2577] 1H NMR (DMSO-d6) δ 2.81 (6H, s), 3.27-3.36 (2H, m), 3.74 (3H, s),3.89-3.96 (2H, m), 5.52 (2H, s), 5.78 (1H, s), 6.15 (1H, t, J=5.7 Hz),6.87-6.92 (4H, m), 7.05-7.15 (4H, m)

[2578] Example 514

[2579] To a solution of4-[3-(dimethylamino)-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenol (98.7mg) in DMF (2 mg) was added sodium hydride 60% dispersion in mineral oil(15.3 mg). The mixture was stirred at ambient temperature for 1 hour. Tothe reaction mixture was added (2-bromoethoxy)-tert-butyldimethylsilane(153 mg) in DMF (1 ml) dropwise and the mixture was stirred at ambienttemperature overnight. The mixture was poured into ice water, extractedwith AcOEt, washed with H2O and saturated aqueous sodium chloridesolution. The aqueous layer was reextracted with AcOEt. The combinedorganic layers were dried over magnesium sulfate, and concentrated invacuo. The residue was dissolved in EtOH (2 mg) . To this solution wasadded concentrated hydrochloric acid (100 μl) and the mixture wasstirred at ambient temperature for 3 hours. The mixture was concentratedinvacuo, and the residue was partitioned between AcOEt and saturatedaqueous sodium bicarbonate solution, washed with saturated aqueoussodium chloride solution, dried over magnesium sulfate, and concentratedin vacuo. The residue was purified by preparative thin layer silica gelchromatography developed by AcOEt/n-hexane =60%. The residual crystalswere collected and washed with IPE to give2-{4-[3-(dimethylamino)-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenoxy}ethanol(97 mg) as a white powder.

[2580] mp. 120-122° C.

[2581] IR (KBr) : 3292, 2924, 1612, 1577, 1562, 1531, 1514 cm−1

[2582] Mass (ESI+) : 354 (M+H)+

[2583] 200 MHz 1H NMR (DMSO-d6, d) : 2.81 (6H, s), 3.66-3.72 (2H, m),3.74 (3H, s), 3.94-4.00 (2H, m), 4.86 (1H, br), 6.02 (1H, s), 6.86-6.94(4H, m), 7.10 (2H, d, J=8.9 Hz), 7.12 (2H, d, J=8.7 Hz)

[2584] The following compound(s) was(were) obtained in a similar mannerto that of Example 514.

[2585] Example 515

[2586]N-[5-[4-(2-hydroxyethoxy)phenyl]-1-(4-methoxyphenyl)-1-H-pyrazol-3-yl]-N,N′,N′-trimethylurea

[2587] oil

[2588] IR (neat) : 3410, 2931, 1658, 1649, 1641, 1631, 1612, 1518, 1502cm−1

[2589] Mass (ESI+) : 411 (M+H)+

[2590] 200 MHz 1H NMR (CDCl3, d) : 2.08 (1H, t, J=5.9 Hz), 2.89 (6H, s),3.33 (3H, s), 3.81 (3H, s), 3.92-4.00 (2H,m),4.05-4.10 (2H, m), 6.15(1H, s), 6.84 (4H, d, J=9.1 Hz), 7.14 (2H, d, J=9.1 Hz), 7.19 (2H, d,J=9.1 Hz)

[2591] Example 516

[2592]2-14-[3-ethoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxylethanol

[2593] white powder : mp. 67.7-69.2° C.

[2594] IR (ATR) : 3363, 2993, 2956, 2925, 2837, 1610, 1577, 1552, 1508cm−1

[2595] Mass (ESI+) : 355 (M+H)+

[2596] 200 MHz 1H NMR (CDCl3, d) : 1.42 (3H, t, J=7.1 Hz), 2.01 (1H, t,J=6.0 Hz), 3.79 (3H, s), 3.92-4.00 (2H, m), 4.04-4.10 (2H, m), 4.29 (2H,q, J=7.1 Hz), 5.87 (1H, s), 6.77-6.85 (4H, m), 7.14 (2H, d, J=8.8 Hz),7.17 (2H, d, J=8.9 Hz))

[2597] Example 517

[2598]2-{4-[3-isobutoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-phenoxy}ethanol

[2599] oil

[2600] Mass (ESI+) : m/z 383 (M+H)+

[2601] 200 MHz 1H NMR (CDCl3, d) : 1.03 (6H, d, J=6.8 Hz), 2.02 (1H, t,J=6.1 Hz), 2.11 (1H, m), 3.79 (3H, s), 3.91-4.09 (4H, m), 3.99 (2H, d,J=6.8 Hz), 5.88 (1H, s), 6.77-6.86 (4H, m), 7.09-7.21 (4H, m)

[2602] Example 518

[2603]2-{4-[3-(2-methoxyethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy)ethanol

[2604] oil

[2605] Mass (ESI+) : 385 (M+H)+

[2606] IR (neat) : 3400, 3390, 3369, 2935, 1612, 1517 cm-1

[2607] 200 MHz 1H NMR (DMSO-d6, d) : 3.31 (3H, s), 3.62-3.73 (4H, m),3.75 (3H, s), 3.94-3.99 (2H, m), 4.22-4.27 (2H, m), 4.85 (1H, t, J=5.5Hz), 6.04 (1H, s), 6.89 (2H, d, J=8.8 Hz), 6.92 (2H, d, J=8.9 Hz),7.08-7.15 (4H, m)

[2608] Example 519

[2609]2-{4-[3-(2-ethoxyethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethanol

[2610] oil

[2611] IR(neat) : 2972, 2933, 2873, 1612, 1554, 1518, 1510 cm−1

[2612] Mass (ESI+) : 399 (M+H)+

[2613] 200 MHz 1H NMR (CDCl3, d) : 1.25 (3H, t, J=7.0 Hz), 2.04 (1H, t,J=6.1 Hz), 3.61 (2H, q, J=7.0 Hz), 3.78-3.83 (2H, m), 3.79 (3H, s),3.93-4.00 (2H, m), 4.04-4.07 (2H, m), 4.38-4.44 (2H,m),5. 92 (1H,s),6.82(4H,d,J=8.8 Hz),7.13 (2H, d, J=8.8 Hz), 7.16 (2H, d, J=8.8 Hz)

[2614] Example 520

[2615]2-{[5-[4-(2-hydroxyethoxy)phenyl]-1-(4-methoxyphenyl)-1-H-pyrazol-3-yl]oxy}-N,N-dimethylacetamide

[2616] white powder : mp. 106.6-107.1° C.

[2617] IR (KBr) 3321, 2939, 1658, 1643, 1608, 1518 cm−1

[2618] MS (ESI+) : m/z 412 (M+H)+

[2619] 200 MHz 1H NMR (DMSO-d6, d) : 2.84 (3H, s), 2.97 (3H, s),3.65-3.73 (2H, m), 3.75 (3H, s), 3.94-4.00 (2H, m), 4.87 (1H, t, J=5.1Hz), 4.87 (2H, s), 6.07 (1H, s), 6.90 (2H, d, J=8.8 Hz), 6.92 (2H, d,J=9.0 Hz), 7.11 (2H, d, J=9.0 Hz), 7.12 (2H, d, J=8.8 Hz)

[2620] Example 521

[2621]2-{4-[3-methoxy-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenoxy}ethanol

[2622] white powder : mp.92.2-92.5° C.

[2623] IR (KBr) : 3325, 1614, 1525, 1504 cm−1

[2624] MS (ESI+) : m/z 342 (M+H)+

[2625] 200 MHz 1HNMR (CDCl3, d) : 2.01 (1H, t, J=6.1 Hz), 3.92-4.10 (4H,m), 3.92 (3H, s), 3.97 (3H, s), 5.91 (1H, s), 6.70 (1H, d, J=8.5 Hz),6.85 (2H, d, J=8.8 Hz), 7.15 (2H, d, J=8.8 Hz), 7.52 (1H, dd, J=2.5,8.5Hz), 8.04 (1H, d, J=2.5 Hz)

[2626] Example 522

[2627]2-{4-[3-ethoxy-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenoxy}ethanol

[2628] white powder : mp. 81-82° C.

[2629] IR (KBr) : 3303, 3298, 1612, 1516 cm−1

[2630] Mass (sample ID cox022145) (ESI+) : 356 (M+H)+

[2631] 200 MHz 1H NMR (DMSO-d6, d) : 1.33 (3H, t, J=7.0 Hz), 3.65-3.74(2H, m), 3.84 (3H, s), 3.95-4.01 (2H, m), 4.19 (2H, q, J=7.0 Hz), 4.87(1H, t, J=5.4 Hz), 6.09 (1H, s), 6.85 (1H, d, J=8.8 Hz), 6.93 (2H, d,J=8.8 Hz), 7.16 (2H, d, J=8.8 Hz), 7.58 (1H, d, J=2.6, 8.8 Hz), 7.99(1H, d, J=2.6 Hz)

[2632] Example 523

[2633] To a solution of 5-(hydroxyl)phenyl-1-(4-methoxyphenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazole(5.0 g) and 2-bromoethoxy-tert-butyldimethylsilane (6.87 g) in DMF (100ml) was added portionwise NaH (919 mg, 50% in oil) at room temperature.The reacion mixture was stirred overnight. The reaction mixture wasquenched with water. Aqueouslayer was extracted twice with EtOAc.Combined organic layer was washed twice with water, andbrine. Dried,filtered and evaporated under reduced pressure to give 5.29 g (73%) of5-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-ethoxy)phenyl]-1-(4-methoxyphenyl)-4-methyl-3-(trifluoromethyl)-1-H-pyrazole.

[2634] MASS (ESI+): m/z =507.1 (M+l), 529.0 (M+Na).

[2635] 1HNMR (400 MHz, CDCl3): .07 (3H, s), .09 (3H, s), .9 (9H, s),2.15 (3H, s), 3.78 (3H, s), 3.62-4.13 (4H, m), 6.79 2H, d, J =8.5 Hz),6.88 (2H, d, J =8.7 Hz), 7.05 (2H, d, J =8.7 Hz), 7.13 (2H, d, J =8.5Hz)

[2636] Example 524

[2637]2-{4-[1-(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl]phenoxy}ethanol

[2638] mp 50.7-51.7° C.

[2639] Mass (ESI+) : 409 (M+H)+

[2640] 1HNMR (200 MHz, CDCl3) : 1.99 (1H, t, J=6.OHz), 3.80 (3H, s),3.92-4.00 (2H, m), 4.05-4.10 (2H, m), 4.62 (1H, d, J=8.5 Hz), 4.70 (1H,d, J =8.5 Hz), 5.95 (1H, s), 6.79-6.92 (4H, m), 7.07-7.18 (4H, m)

[2641] Example 525

[2642]2-{4-[3-(2,2-difluoroethoxy)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethanol

[2643] oil

[2644] Mass (ESI+) : 391 (M+H)

[2645] 1HNMR (200 MHz, CDCl3): 1.99 (1H, t, J =6.1 Hz), 3.80 (3H, s),3.92-4.00 (2H, m), 4.05-4.09 (2H, m), 4.47 (2H, dt, J =4.2 ,13.5 Hz),5.92 (1H, s), 6.17 (1H, tt, J =4.2,55.5 Hz), 6.79-6.87 (4H, m),7.09-7.20 (4H, m)

[2646] Example 526

[2647]2-{4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoro-ethoxy)-1-H-pyrazol-5-yl]phenoxy}ethanol

[2648] mp. 91.2-91.3° C.

[2649] Mass (sample ID coxO31168) (ESI+) : 410 (M+H)+

[2650] 1HNMR (200 MHz, CDCl3) : 1.99 (1H, t, J =6.1 Hz), 3.91 (3H, s),3.92-4.01 (2H, m), 4.06-4.11 (2H, m), 4.61 (1H, d, J =8.4 Hz), 4.70 (1H,d, J =8.4 Hz), 5.98 (1H, s), 6.71 (1H, d, J =8.8 Hz), 6.86 (2H, d, J=8.8 Hz), 7.14 2H, d, J =8.8 Hz), 7.48 (1H, dd, J =2.7 ,8.8 Hz), 8.021H, d, J =2.7 Hz)

[2651] Example 527

[2652]2-{4-[3-(2,2-difluoroethoxy)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenoxy}ethanol

[2653] oil

[2654] Mass (ESI+) : 392 (M+H)

[2655] 1HNMR (200 MHz, CDCl3): 3.92 (3H, s), 3.93-4.00 (2H, m),4.06-4.11 (2H, m), 4.46 (2H, dt, J =4.2 ,13.2 Hz), 5.94 (1H, s), 6.17(1H, tt, J =4.2, 55.5 Hz), 6.71 (1H, d, J =9.0 Hz), 6.86 (2H, d, J =8.9Hz), 7.14 (2H, d, J =8.9 Hz), 7.48 (1H, dd, J =2.7 , 9.0 Hz), 8.02 (1H,d, J =2.7 Hz)

[2656] Example 528

[2657] Carbonyldiimidazole (1.26 g) was added to a solution of5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-3-amino-1-H-pyrazole (2.4 g)in 1-methyl-2-pyrrolidinone (22 mg). After stirring at ambienttemperature for 2 hour, 2M solution of dimethylamine in THF (7.4 mg) wasadded and the mixture was stirred ambient temperature for 2 hour. Thereaction mixture was partitioned between ethyl acetate and H2O. Theorganic layer was washed with saturated aqueous sodium chloridesolution, dried over magnesium sulfate, and concentrated in vacuo. Theresidue was purified by silica gel column chromatography eluted withAcOEt/n-hexane =80% to giveN′-[5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-1-H-pyrazol-3-yl]-N,N-dimethylurea(2.35 g) as amorphous powder.

[2658] Mass (ESI+) : 443 (M+H)+

[2659] 200 MHz 1HNMR (DMSO-d6, d) : 2.91 (6H, s), 3.76 (3H, s), 5.09(2H, s), 6.63 (1H, s), 6.93 (2H, d, J=9.0 Hz), 6.98 (2H, d, J=9.0 Hz),7.14 (2H, d, J=9.0 Hz), 7.15 (2H, d, J=9.0 Hz), 7.34-7.44 (5H, m), 9.02(1H, s)

[2660] Example 529

[2661] A mixture ofN′-[5-[4-(hydroxy)phenyl]-1-(4-methoxyphenyl)-1-H-pyrazol-3-yl]-N,N-dimethylurea(121.9 mg), 2- (tert-butyl- dimethylsilyloxy) ethyl bromide (166 mg),and K2CO3 (95.6 mg) in DMF (1.5 mg) was stirred at 75° C. for 7 hours.2-(tert-butyldimethylsilyloxy)ethyl bromide (83 mg) and KI (57.4 mg) wasadded to the reaction mixture, and the mixture was stirred at 75° C.overnight. The mixture was allowed to cool to ambient temperature, andwas partitioned between ethyl acetate and H2. The aqueous layer wasreextracted with ethyl acetate. The combined organic layer was washedwith saturated aqueous sodium chloride solution, dried over magnesiumsulfate, and concentrated in vacuo. The residue was purified bypreparative thin layer silica gel chromatography developed by 5%MeOH/CHCl3. The seaparated silica gel was extracted with 10% MeOH/CHCl3and the solvent was evaporated in vacuo to giveN′-[5-[4-(2-hydroxyethoxy)phenyl]-1-(4-methoxyphenyl)-1-H-pyrazol-3-yl]-N,N-dimethylurea(115 mg) as an amorphous powder. 84.3 mg of amorphous powder wascrystallized from AcOEt-IPE to giveN′-[5-[4-(2-hydroxyethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,N-dimethylurea(79.5 mg) as a white powder.

[2662] mp. 167.4-167.6° C.

[2663] IR (KBr) : 3317, 1670, 1612, 1587, 1572, 1510 cm−1

[2664] Mass (ESI+) : 397 (M+H)+200 MHz 1H NMR (DMSO-d6, d) : 2.91 (6H,s), 3.65-3.74 (2H, m), 3.76 (3H,-s),3.94-4.00 (2H,m),4.87 (1H,t,J=5.5Hz), 6.62 (1H, s), 6.90 (2H, d, J=8.7 Hz), 6.93 (2H, d, J=8.9 Hz), 7.12(2H, d, J=8.7 Hz), 7.15 (2H, d, J=8.9 Hz), 9.02 (1H, s)

[2665] Example 530

[2666] Diethylazodicarboxylate 308 mg was added to a solution ofN′-[5-[4-(hydroxy)-phenyl]-1-(4-methoxyphenyl)-1-H-pyrazol-3-yl]-N,N-dimethylurea415 mg, tert-butyl N- (2-hydroxyethyl) carbamate 380 mg, andtriphenylphosphine 463 mg in THF 5 mg. After stirring at ambienttemperature for overnight, the reaction mixture was concentrated invacuo. To a solution of the residue in CH2Cl2 5 mg, was added 4Maolution of HCl in dioxane 5 mg. After stirring at ambient temperaturefor 1.5 hours, the reaction mixture was concentrated in vacuo. Theresidue was partitioned between AcOEt and 1M HCl. The aqueous layer wasreextracted with AcOEt and concentrated in vacuo. The remained H2wasevaporated azeotropically with toluene to giveN′-[5-[4-(2-aminoethoxy)phenyl]-1-(4-methoxyphenyl)-1-H-pyrazol-3-yl]-N,N-dimethylureahydrochloride 580 mg as an amorphous powder.

[2667] Mass (ESI+) : 396 (M+H)+

[2668] 200 MHz 1HNMR (DMSO-d6, d) : 2.91 (6H, s), 3.15-3.24 (2H, m),3.76 (3H, s), 4.14-4.21 (2H, m), 6.64 (1H, s), 6.94 (2H, d, J=8.9 Hz),6.95 (2H, d, J=8.7 Hz), 7.15 (2H, d, J=8.9 Hz), 7.17 (2H, d, J=8.7 Hz),8.20 (2H, brs), 9.04 (1H, s)

[2669] The following compound(s) was(were) obtained in a similar mannerto that of Example 530.

[2670] Example 531

[2671]N-[5-[4-(2-aminoethoxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,N′, N′-trimethylurea hydrochloride

[2672] amorphous

[2673] Mass (ESI+) : 410 (M+H)+

[2674] 200 MHz 1H NMR (DMSO-d6, d) 2.79 (6H, s), 3.13 (3H, s), 3.14-3.24(2H, m), 3.80 (3H, s), 4.15-4.20 (2H, m), 6.27 (1H, s), 6.94 (2H, d,J=8.6 Hz), 6.94 (2H, d, J=8.9 Hz), 7.16 (2H, d, J=8.9 Hz), 7.19 (2H, d,J=8.6 Hz), 8.24 (2H, brs)

[2675] Example 532

[2676]2-{[5-[4-(2-aminoethoxy)phenyl]-1-(4-methoxyphenyl)-1-H-pyrazol-3-yl]oxy}-N,N-dimethylacetamidehydrochloride

[2677] amorphous

[2678] MS (ESI+) : m/z 411 (M+H)+

[2679] 200 MHz 1H NMR (DMSO-d6, d) : 2.84 (3H, s), 2.97 (3H, s),3.14-3.24 (2H, m), 3.76 (3H, s), 4.14-4.20 (2H, m), 4.88 (2H, s), 6.09(1H, s), 6.93 (2H, d, J=9.0 Hz), 6.95 (2H, d, J=8.8 Hz), 7.07-7.29 (4H,m), 8.21 (2H, brs)

[2680] Example 533

[2681] A solution of potassium cyanate (64.9 mg) in H2(0.5 mg) was addedto a solution ofN′-[5-[4-(2-aminoethoxy)phenyl]-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-N,N-dimethylureahydrochloride (172.8 mg) and sodium acetate (65.6 mg) in a mixture ofDMF (1.5 mg) and H2O (0.5 mg). The reaction mixture was stirred atambient temperature overnight. The mixture was diluted with H2O,partitioned between AcOEt and H2O. The aqueous layer was reextractedwith AcOEt. saturated aqueous sodium chloride solution, dried overmagnesium sulfate, and concentrated in vacuo. The residue was purifiedby preparative thin layer silica gel chromatography developed by 10%MeOH/CHCl3. The seaparated silica gel was extracted with 10% MeOH/CHCl3and the solvent was evaporated in vacuo. The residue was crystallizedfrom AcOEt-IPE to give N′-[5-(4-{2-[(aminocarbonyl)-amino]ethoxy}phenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,N-dimethylurea(87.0 mg) as a powder.

[2682] mp. 193-196° C.

[2683] IR (KBr) : 3437, 3421, 1660, 1649, 1620, 1612, 1581, 1562, 1554,1529, 1512 cm−

[2684] Mass (ESI+) : 439 (M+H)+

[2685] 200 MHz 1H NMR (DMSO-d6, d) : 2.91 (6H, s), 3.27-3.34 (2H, m),3.76 (3H, s), 3.93 (2H, t, J=5.5 Hz), 5.53 (2H, s), 6.16 (1H, t, J=5.7Hz), 6.62 (1H, s), 6.91 (2H, d, J=8.7 Hz), 6.93 (2H, d, J=8.9 Hz), 7.13(2H, d, J=8.7 Hz), 7.15 (2H, d, J=8.9 Hz), 9.02 (1H, s)

[2686] The following compound(s) was(were) obtained in a similar mannerto that of Example 533.

[2687] Example 534

[2688]N-[5-(4-{2-[(aminocarbonyl)amino]ethoxy}phenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N,N′, N′-trimethylurea

[2689] powder : mp. 158.6-159.0° C.

[2690] IR (KBr) :3433, 3369, 1687, 1658, 1643, 1612, 1514, 1500 cm−1

[2691] Mass (ESI+) : 453 (M+H)+

[2692] 200 MHz 1H NMR (DMSO-d6, d) : 2.79 (6H, s), 3.12 (3H, s),3.27-3.34 (2H,m),3.76 (3H,s),3.93 (2H,t,J=5.5 Hz), 5.53 (2H, s), 6.15(1H, t, J=5.6 Hz), 6.25 (1H, s), 6.91 (2H, d, J=8.7 Hz), 6.94 (2H, d,J=8.9 Hz), 7.15 (2H, d, J=8.7 Hz), 7.15 (2H, d, J=8.9 Hz)

[2693] Example 535

[2694]N-(2-{4-[3-(2-methoxyethoxy)-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)urea

[2695] white powder : mp. 131-132° C.

[2696] IR (KBr) : 3435, 3429, 3388, 3350, 1658, 1612, 1562, 1554, 1518cm−1

[2697] Mass (sample ID coxO22116) (ESI+) : 427 (M+H)+

[2698] 200 MHz 1H NMR (DMSO-d6, d) : 3.28-3.38 (2H, m), 3.30 (3H, s),3.62-3.68 (2H, m), 3.75 (3H, s), 3.89-3.96 (2H, m), 4.21-4.27(2H,m),5.53 (2H,s),6.05 (1H,s), 6.15 (1H,t,J=5.7 Hz), 6.91 (2H, d, J=8.9Hz), 6.92 (2H, d, J=9.0 Hz), 7.10-7.15 (4H, m)

[2699] Example 536

[2700]N-(2-{4-[3-(2-ethoxyethoxy)-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)urea

[2701] white powder : mp. 124.1-124.2° C.

[2702] IR (KBr) : 3388, 3379, 3340, 1657, 1643, 1612, 1562, 1554, 1518cm−1

[2703] Mass (ESI+) : 441 (M+H)+

[2704] 200 MHz 1H NMR (DMSO-d6, d) : 1.13 (3H, t, J=7.0 Hz), 3.27-3.36(2H, m), 3.49 (2H, q, J=7.0 Hz), 3.66-3.71 (2H, m), 3.75 (3H, s),3.89-3.96 (2H, m), 4.21-4.26 (2H, m), 5.53 (2H, s), 6.06 (1H, s), 6.15(1H, t, J=5.7 Hz), 6.91 (2H, d, J=8.8 Hz), 6.92 (2H, d, J=9.0 Hz),7.10-7.15 (4H, m)

[2705] Example 537

[2706]2-{[5-(4-{2-[(aminocarbonyl)amino]ethoxy}phenyl)-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]oxy}-N,N-dimethyl-acetamide

[2707] white powder : mp.223-227° C.

[2708] IR (KBr) : 3402, 3332, 3201, 3194, 2925, 1664, 1612, 1518, 1502cm−1

[2709] MS (ESI+) : m/z 454 (M+H)+

[2710] 200 MHz 1H NMR (DMSO-d6, d) : 2.84 (3H, s), 2.97 (3H, s),3.27-3.35 (2H, m), 3.75 (3H, s), 3.89-3.96 (2H, m), 4.87 (2H, s), 5.53(2H, s), 6.07 (1H, s), 6.15 (1H, t, J=5.5 Hz), 6.91 (2H, d, J=8.9 Hz),6.93 (2H, d, J=9.0 Hz), 7.11 (2H, d, J=9.0 Hz), 7.13 (2H, d, J=8.9 Hz)

[2711] Example 538

[2712]N-(2-{4-[3-methoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea

[2713] white powder : mp. 192.6-192.7° C. IR (KBr) : 3390, 3352, 3311,3305, 1657, 1610, 1583, 1568, 1525, 1502 cm−1

[2714] MS (ESI+) : m/z 384 (M+H)+

[2715] 200 MHz 1H NMR (DMSO-d6, d) : 3.27-3.36 (2H, m), 3.34 (3H, s),3.85 (3H, s), 3.91-3.97 (2H, m), 5.53 (2H, s), 6.11 (1H, s), 6.15 (1H,t, J=5.7 Hz), 6.85 (1H, d, J=8.7 Hz), 6.94 (2H, d, J=8.8 Hz), 7.17 (2H,d, J=8.8 Hz), 7.59 (1H, dd, J=2.6,8.7 Hz), 8.00 (1H, d, J=2.6 Hz)

[2716] Example 539

[2717]N-(2-{4-[3-ethoxy-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)urea

[2718] white powder : mp. 133-138° C.

[2719] IR (KBr) : 3350, 1657, 1643, 1612, 1579, 1562, 1554, 1518, 1500cm-1; MS (ESI+) : m/z 398 (M+H)+

[2720] 200 MHz 1H NMR (DMSO-d6, d) : 1.33 (3H, t, J=7.0 Hz), 3.28-3.35(2H, m), 3.84 (3H, s), 3.91-3.97 (2H, m), 4.19 (2H, q, J=7.0 Hz), 5.53(2H, s), 6.09 (1H, s), 6.16 (1H, t, J=5.6 Hz), 6.85 (1H, d, J=8.8 Hz),6.94 (2H, d, J=8.8 Hz), 7.17 (2H, d, J=8.8 Hz), 7.58 (1H, dd, J=2.7,8.8Hz), 8.00 (1H, d, J=2.7 Hz)

[2721] Example 540

[2722]N-(2-{4-[3-cyclopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)urea

[2723] mp. 94-96° C.

[2724] MS (ESI+) : m/z 394 (M+H)

[2725] 1HNMR (200 MHz, DMSOd6): 0.72-0.78 (2H, m), 0.87-0.95 (2H, m),1.87-2.01 (1H, m), 3.23-3.42 (2H, m), 3.85 (3H, s), 3.90-3.97 (2H, m),5.52 (2H, s), 6.12 (1H, t, J =5.6 Hz), 6.30 (1H, s), 6.85 (1H, d, J =8.8Hz), 6.92 (2H, d, J =8.7 Hz), 7.13 (2H, d, J =8.7 Hz), 7.58 1H, dd, J=2.7 ,8.8 Hz), 8.01 (1H, d, J =2.7 Hz)

[2726] Example 541

[2727]N-(2-{4-[1-(4-methoxyphenyl)-3-(1-piperidinylcarbonyl)-1H-pyrazol-5-yl]phenoxylethyl)urea

[2728] mp.152.0-152.2° C.

[2729] Mass (ESI+) : 464 (M+H)

[2730] 1HNMR (200 MHz, DMSOd6) : 1.42-1.73 (6H, m), 3.27-3.36 (2H, m),3.53-3.67 (2H, m), 3.73-3.96 (2H, m), 3.78 (3H, s), 3.90-3.97 (2H, m),5.51 (2H, s), 6.14 (1H, t, J =5.7 Hz), 6.77 (1H, s), 6.92 (2H, d, J =8.8Hz), 6.98 (2H, d, J =9,0 Hz), 7.17 (2H, d, J =8.8 Hz), 7.23 (2H, d, J=9.0 Hz)

[2731] Example 542

[2732]N-(2-{4-[1-(6-methoxy-3-pyridinyl)-3-(1-piperidinyl-carbonyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)urea

[2733] mp.164-167° C.

[2734] Mass (ESI+) : 465 (M+H)

[2735] 1HNMR (200 MHz, DMSOd6): 1.42-1.73 (6H, m), 3.22-3.40 (2H, m),3.52-3.70 (2H, m), 3.75-3.95 (2H, m), 3.87 (3H, s), 3.92-3.98 (2H, m),5.52 (2H, s), 6.15 (1H, t, J =5.6 Hz), 6.81 (1H, s), 6.90 (1H, d, J =8.9Hz), 6.95 (2H, d, J =8.8 Hz), 7.21 (2H, d, J =8.8 Hz), 7.67 1H, dd, J=2.7 ,8.9 Hz), 8.14 (1H, d, J =2.7 Hz)

[2736] Example 543

[2737]5-(4-{2-[(aminocarbonyl)amino]ethoxy}phenyl)-N-ethyl-1-(6-methoxy-3-pyridinyl)-N-methyl-1H-pyrazole-3-carboxamide

[2738] mp.146.3-146.7° C.

[2739] MS (ESI+) : m/z 439 (M+H)

[2740] 1HNMR (200 MHz, DMSOd6): 1.09-1.23 (3H, m), 2.98, 3.28 (3H, s),3.28-3.37 (2H, m), 3.40-3.53, 3.63-3.77 (2H, m), 3.87 (3H, s), 3.92-3.98(2H, m), 5.52 (2H, s), 6.15 (1H, t, J =5.5 Hz), 6.82, 6.85 (1H, s), 6.90(1H, d, J =9.0 Hz), 6.95 (2H, d, J=8.7 Hz), 7.21 (2H, d, J =8.7 Hz),7.60-7.73 (1H, m), 8.14-8.16 (1H, m)

[2741] Example 544

[2742]N-(2-{4-[1-(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1-H-pyrazol-5-yl]phenoxylethyl)urea

[2743] mp.130-132° C.

[2744] MS (ESI+) : m/z 451 (M+H)

[2745] 1HNMR (200 MHz, DMSOd6) : 3.27-3.33 (2H, m) , 3.76 (3H, s),3.90-3.96 (2H, m), 4.81 (1H, d, J =9.0 Hz), 4.90 (1H, d, J=9.0 Hz), 5.52(2H, s), 6.14 (1H, t, J =5.6 Hz), 6.21 (1H, s), 6.89-6.98 (4H, m),7.12-7.18 (4H, m)

[2746] Example 545

[2747]N-(2-{4-[3-(2,2-difluoroethoxy)-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)urea

[2748] mp. 138.6-139.1° C.

[2749] MS (ESI+) : m/z 432 (M+H)

[2750] 1HNMR (200 MHz, DMSOd6): 3.27-3.36 (2H, m), 3.76 (3H, s),3.90-3.96 (2H, m), 4.44 (2H, dt, J =3.5 ,14.9 Hz), 5.52 (2H, s),6.11-6.17 (1H, m), 6.15 (1H, s), 6.41 (1H, tt, J =3.5, 54.6 Hz), 6.91(2H, d, J =8.9 Hz), 6.93 (2H, d, J 8.9 Hz), 7.14 (2H, d, J =8.9 Hz),7.15 (2H, d, J =8.9 Hz)

[2751] Example 546

[2752]N-(2-(4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoro-ethoxy)-1-H-pyrazol-5-yl]phenoxy}ethyl)urea

[2753] mp. 134.8-134.9° C.

[2754] MS (ESI+) : m/z 452 (M+H)

[2755] 1HNMR (200 MHz, ): 3.24-3.39 (2H, m), 3.85 (3H, s), 3.91-3.98(2H, m), 4.83 (1H, d, J =9 Hz), 4.92 (1H, d, J =9 Hz), 5.52 (2H, s),6.15 (1H, t, J=5.6 Hz), 6.27 (1H, s), 6.87 (1H, d, J =8.8 Hz), 6.95 (2H,d, J =8.8 Hz), 7.18 (2H, d, J =8.8 Hz), 7.61 (1H, dd, J =2.7 ,8.8 Hz),8.04 (1H, d, J =2.7 Hz)

[2756] Example 547

[2757]N-(2-{4-[3-(2,2-difluoroethoxy)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)urea

[2758] mp.146.9-147.3° C.

[2759] MS (ESI+) : m/z 434 (M+H)

[2760] 1HNMR (200 MHz, DMSOd6): 3.23-3.40 (2H, m), 3.85 (3H, s),3.91-3.97 (2H, m), 4.45 (2H, dt, J =3.5 ,14.9 Hz), 5.52 (2H, s), 6.15(1H, t, J =5.7 Hz), 6.21 (1H, s), 6.42 (1H, tt, J =3.5, 54.6 Hz), 6.86(1H, d, J =8.8 Hz), 6.94 (2H, d, J=8.8 Hz), 6.94 (2H, d, J =8.8 Hz),7.60 1H, dd, J =2.8 ,8.8 Hz), 8.03 (1H, d, J =2.8 Hz)

[2761] Example 548

[2762]5-(4-{[(aminocarbonyl)amino]methyl}phenyl)-N-ethyl-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole-3-carboxamide

[2763] mp.184.7-185.1° C.

[2764] MS (ESI+) : m/z 408 (M+H)

[2765] 1HNMR (200 MHz, DMSOd6): 1.09-1.22 (3H, m), 2.98, 3.29 3H, s),3.41-3.78 (2H, m), 3.78 (3H, s), 4.16 (2H, d, J=6.OHz ),5.54 (2H, s),6.44 (1H, t, J =6 Hz), 6.84, 6.86 (1H, s), 6.99 (2H, d, J =8.9 Hz),7.2-7.27 (6H, m)

[2766] Example 549

[2767] N-{4-[3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]benzyl}urea

[2768] amorphous powder

[2769] MS (ESI+) : m/z 365 (M+H)

[2770] 1HNMR (200 MHz, DMSOd6): 1.27 (6H, d, J =7.OHz ), 2.95 (1H, m),3.76 (3H, s), 4.15 (2H, d, J =6.0 Hz), 5.53 (2H, s), 6.42 (1H, t, J =6.0Hz), 6.44 (1H, s), 6.93 (2H, d, J =8.9 Hz), 7.11-7.22 (6H, m)

[2771] Example 550

[2772]N-{4-[1-(6-methoxy-3-pyridinyl)-3-(1-piperidinyl-carbonyl)-1-H-pyrazol-5-yl]benzyl}urea

[2773] mp.178.9-178.9° C.

[2774] MS (ESI+) : m/z 435 (M+H)

[2775] 1HNMR (400 MHz, DMSOd6) : 1.47-1.70 (6H, m), 3.55-3.66 (2H, m),3.78-3.89 (2H, m), 3.87 (3H, s), 4.17 (2H, d, J =6.0 Hz ), 5.55 (2H, s),6.45 (1H, t, J =6.0 Hz), 6.86 (1H, s), 6.91 (1H, d, J =8.8 Hz), 7.24(4H, s), 7.70 (1H, dd, J =2.7 ,8.8 Hz), 8.14 (1H, d, J =2.7 Hz)

[2776] Example 551

[2777]5-(4-{[(aminocarbonyl)amino]methyl}phenyl)-N-ethyl-1-(6-methoxy-3-pyridinyl)-N-methyl-1H-pyrazole-3-carboxamide

[2778] mp.172.6-172.8° C.

[2779] MS (ESI+) : m/z 409 (M+H)

[2780] 1HNMR (400 MHz, DMSOd6): 1.13 , 1.19 (3H, t, J =7.0 Hz) 2.98,3.29 (3H, s), 3.48, 3.72 (2H, q, J =7.0 Hz), 3.87 (3H, s), 4.18 (2H, d,J =6.0 Hz), 5.55 (2H, s), 4.45 (1H, t, J =6.OHz ), 6.87-6.93 (2H, m),7.24 (4H, s), 7.67-7.73 (1H, m), 8.14-8.16 (1H, m)

[2781] Example 552

[2782]N-{4-[3-isopropyl-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]benzyl}urea

[2783] mp.139-144° C.

[2784] MS (ESI+) : m/z 366 (M+H)

[2785] 1HNMR (200 MHz, DMSOd6): 1.27 (6H, d, J =7.0 Hz), 2.97 (1H, m),3.85 (3H, s), 4.17 (2H, d, J =6.OHz ), 5.53 (2H, s), 6.43 (1H, t, J =6.0Hz ), 6.5 0 (1H, s), 6.86 (1H, d, J =8.8 Hz), 7.15-7.26 (4H, m), 7.62(1H, dd, J =2.8 ,8.8 Hz), 8.02 (1H, d, J =2.7 Hz)

[2786] Example 553

[2787]N-{4-[3-isobutyryl-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]benzyl}urea

[2788] mp.157.0-157.3° C.

[2789] MS (ESI+) : m/z 394 (M+H)

[2790] 1HNMR (200 MHz, DMSOd6): 1.16 (6H, d, J =6.8 Hz), 3.68 (1H, m),3.88 (3H, s), 4.17 (2H, d, J =6.OHz ), 5.54 (2H, s), 6.45 (1H, t, J =6.0Hz), 6.93 (1H, d, J =8.8 Hz), 7.06 (1H, s), 7.25 (4H, s), 7.76 (1H, dd,J =2.7 ,8.8 Hz), 8.18 (1H, d, J =2.7 Hz)

[2791] Example 554

[2792] N-{4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5yl]benzyl}urea

[2793] mp.206.0-260.9° C.

[2794] MS (ESI+) : m/z 353 (M+H)

[2795] 1HNMR (200 MHz, DMSOd6): 3.76 (3H, s), 3.84 (3H, s), 4.15 (2H, d,J =6.0 Hz), 5.53 (2H, s), 6.09 (1H, s), 6.42 (1H, t, J =6.OHz ), 6.93(2H, d, J =9 Hz), 7.12-7.23 (6H, m)

[2796] Example 555

[2797]N-{4-[3-isopropoxy-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]benzyl}urea

[2798] solid

[2799] MS (ESI+) : m/z 381 (M+H)

[2800] 1HNMR (200 MHz, DMSOd6): 1.31 (6H, d, J =6.1 Hz), 3.76 (3H, s),4.15 (2H, d, J =6.0 Hz ), 4.76 (1H, m), 5.53 (2H, s), 6.04 (1H, s), 6.43(1H, t, J =6.0 Hz), 6.92 (2H, d, J =8.9 Hz), 7.10-7.22 (6H, m)

[2801] Example 556

[2802] N-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]-benzyl}urea

[2803] mp.125.5-126.2° C.

[2804] Mass (ESI+) : 357 (M+H)

[2805] 1HNMR (200 MHz, DMSOd6) : 3.78 (3H, s), 4.15 (2H, d, J =6.1 Hz),5.54 (2H, s), 6.43 (1H, t, J=6.1 Hz), 6.73 (1H, s), 6.97 (2H, d, J =8.9Hz), 7.14-7.24 (6H, m)

[2806] Example 557

[2807]N-{4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]benzyl}urea

[2808] mp.111-115° C.

[2809] Mass (ESI+) : 358 (M+H)

[2810] 1HNMR (200 MHz, DMSOd6): 3.87 (3H, s), 4.17 (2H, d, J =6.0 Hz),5.54 (2H, s), 6.44 (1H, t, J =6.0 Hz), 6.79 (1H, s), 6.89 (1H, d, J =.8Hz), 7.23 (4H, s), 7.69 (1H, dd, J =2.7 ,8.8 Hz), 8.11 (1H, d, J =2.7Hz)

[2811] Example 558

[2812]N-(2-{4-[1-(4-methoxyphenyl)-4-methyl-1H-pyrazol-5-yl]-phenoxy}ethyl)urea

[2813] amorphous powder

[2814] MS (ESI+) : m/z 367 (M+H)

[2815] 1HNMR (400 MHz, DMSOd6): 2.02 (3H, s), 3.32-3.36 (2H, m), 3.74(3H, s), 3.92 -3.96 (2H, m), 5.51 (2H, s), 6.15 (1H, t, J =5.6 Hz), 6.89(2H, d, J =8.9 Hz), 6.94 (2H, d, J =8.8 Hz), 7.08 (2H, d, J =8.8 Hz),7.09 (2H, d, J =8.9 Hz), 7.55 (1H, s)

[2816] Example 559

[2817]N-(2-{4-[1-(6-methoxy-3-pyridinyl)-4-methyl-1H-pyrazol-5-yl]phenoxy}ethyl)urea

[2818] powder

[2819] MS (ESI+) : m/z 368 (M+H)

[2820] 1HNMR (400 MHz, DMSOd6): 2.03 (3H, s), 3.31-3.36 (2H, m), 3.83(3H, s), 3.94 -3.98 (2H, m), 5.51 (2H, s), 6.15 (1H, t, J =5.6 Hz), 6.82(1H, d, J =8.8 Hz), 6.97 (2H, d, J =8.8 Hz), 7.13 (2H, d, J =8.8 Hz),7.53 (1H, dd, J =2.7 ,8.8 Hz), 7.62 (1H, s), 7.98 (1H, d, J =2.7 Hz)

[2821] Example 560

[2822]N-(2-{4-[1-(4-methoxyphenyl)-3-(methylthio)-1H-pyrazol-5-yl]phenoxy}ethyl)urea

[2823] mp. 141.2-142.2° C.

[2824] MS (ESI+) : m/z 399 (M+H)

[2825] 1HNMR (200 MHz, DMSOd6) 2.50 (3H, s), 3.27-3.36 (2H, m), 3.77(3H, s), 3.90-3.96 (2H, m), 5.52 (2H, s), 6.14 (1H, t, J=5.6 Hz), 6.56(1H, s), 6.91 (2H, d, J =8.-8 Hz), 6.95 (2H, d, J =8.8 Hz), 7.14 (2H, d,J =8.8 Hz), 7.17 (2H, d, J =8.8 Hz)

[2826] Example 561

[2827]N-(2-{4-[1-(6-methoxy-3-pyridinyl)-3-(trifluoromethyl)-1-H-pyrazol-5-yl]phenyl)ethyl)urea

[2828] mp.205-206° C.

[2829] MS (ESI+) : m/z 406 (M+H)

[2830] 1HNMR (200 MHz, DMSOd6): 2.64 -2.72 (2H, m), 3.13-3.24 (2H, m),3.88 (3H, s), 5.42 (2H, s), 5.95 (1H, t, J =5.6 Hz), 6.92 (1H, d, J =8.9Hz), 7.17 (1H, s), 7.24 (4H, s), 7.75 (1H, dd, J =2.8 ,8.9 Hz), 8.19(1H, d, J =2.8 Hz)

[2831] Example 562

[2832]

[2833]5-(4-{2-[(aminocarbonyl)amino]ethyl}phenyl)-N-methoxy-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole-3-carboxamide

[2834] oil

[2835] MS (ESI+) : m/z 243 (M+H)

[2836] 1HNMR (200 MHz, CDCl3) : 2.75-2.82 (2H, m), 3.34-3.45 (2H, m),3.51 (3H, s), 3.82 (3H, s), 3.83 (3H, s), 4.46 (2H, s), 4.92 (1H, t, J=5.5 Hz), 6.84 (2H, d, J=9.0 Hz), 6.92 (1H, s), 7.11 (4H, s), 7.15 (2H,d, J =9.0 Hz)

[2837] Example 563

[2838]5-(4-{2-[(aminocarbonyl)amino]ethyl}phenyl)-N-methoxy-1-(6-methoxy-3-pyridinyl)-N-methyl-1H-pyrazole-3-carboxamide

[2839] oil

[2840] MS (ESI+) : m/z 425 (M+H)

[2841] 1HNMR (200 MHz, CDCl3): 2.78-2.86 (2H, m), 3.39-3.49 (2H, m),3.49 (3H, s), 3.85 (3H, s), 3.94 (3H, s), 4.39 (2H, s), 4.70 (1H, t,J=5.8 Hz), 6.75 (1H, d, J=8.9 Hz), 6.80 (1H, s),7.12-7.23 (4H, m) ,7.56(1H, dd, J=2.7 ,8.9 Hz), 8.05 (1H, d, J =2.7 Hz)

[2842] Example 564

[2843] Sodium hydride 60% dispersion in mineral oil 93.1 mg was added inone portion to a solution ofN-[5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]-N′,N′-dimethylurea 1.43 gi n DMF 10 ml under ice bath cooling. The reactionmixture was stirred at ambient temperature for 1 hour. MeI 688 mg wasadded the reaction mixture was stirred at ambient temperature overnight.The mixture was partitioned between ethyl acetate and H2O. The organiclayer was washed with saturated aqueous sodium chloride solution, driedover magnesium sulfate, and concentrated in vacuo. The residue waspurified by silica gel column chromatography eluted withAcOEt-n-hexane=75%, 80% to giveN-[5-[4-(benzyloxy)phenyl]-1-(4-methoxy-phenyl)-1-H-pyrazol-3-yl]-N, N′,N′-trimethylurea 1.45 g as an oil.

[2844] Mass (ESI+) : 457 (M+H)+

[2845] 200 MHz 1HNMR (DMSO-d6,d) :2.79 (6H, s), 3.12 (3H, s), 3.77 (3H,s), 5.09 (2H, s), 6.25 (1H,s), 6.91-7.00 (4H,m),7.14-7.19 (4H, m),7.32-7.46 (5H, m)

[2846] Example 565

[2847] A mixture of N-(2-{4-[3-amino-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)urea 111 mg, lithium chloride 64 mg, and copper(II)chloride 81.2 mg in acetonitrile 2 mg was stirred at ambient temperaturefor 10 minutes. To this mixture was added isoamyl nitrite 62.3 mg, andthe mixture was stirred at ambient temperature for 3 hours. The mixturewas partitioned between ethyl acetate and saturated aqueous ammoniumchloride solution. The organic layer was washed with saturated aqueousammonium chloride solution, H2O, and saturated aqueous sodium chloridesolution, dried over magnesium sulfate, and concentrated in vacuo. Theresidue was purified by preparative thin layer silica gel chromatographydeveloped by MeOH/CHCl3=10%. The seaparated silica gel was extractedwith 10% MeOH/CHCl3 and the solvent was evaporated in vacuo. The residuwas crystallized from AcOEt/IPE to giveN-(2-{4-[3-chloro-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxylethyl)urea 31.1 mg as a white powder.

[2848] mp. 140-142° C.

[2849] Mass (ESI+) : 386 (M+H)+

[2850] 200 MHz 1H NMR (DMSO-d6, d) : 3.27-3.34 (2H, m), 3.77 (3H, s),3.93 (2H, t, J=5.5 Hz), 5.52 (2H, s), 6.15 (1H, t, J=5.7 Hz), 6.68 (1H,s), 6.92 (2H, d, J=9.0 Hz), 6.97 (2H, d, J=9.0 Hz), 7.15 (2H, d, J=9.0Hz), 7.20 (2H, d, J=9.0 Hz))

[2851] Example 566

[2852] Diethyl azodicarboxylate (0.17 mg) was added dropwise to asuspension of3-methoxy-1-(4-methoxyphenyl)-5-(4-hydroxyphenyl)-1H-pyrazole (215.6mg), tert-butyl N-(2-hydroxyethyl)carbamate (352 mg), andtriphenylphosphine (286 mg) in THF (3 mg). The mixture was stirred atambient temperature for 7 hours. Triphenylphosphine (19.1 mg) anddiethyl azodicarboxylate (11.5 μl) were added and the mixture stirred atambient temperature overnight. The mixture was concentrated in vacuo.The residue was purified by silica gel column chromatography eluted withAcOEt/n-hexane=30% to give tert-butyl(2-(4-[3-methoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)carbamate(319 mg) as an oil.

[2853] Mass (ESI+) : 440 (M+H)+

[2854] 200 MHz 1H NMR (CDCl3, d) : 1.45 (9H, s), 3.47-3.56 (2H, m), 3.80(3H, s), 3.96-4.03 (2H, m), 3.97 (3H, s), 4.96 (1H, brs), 5.87 (1H, s),6.79 (2H, d, J=8.8 Hz), 6.82 (2H, d, J=8.9 Hz), 7.09-7.20 (4H, m)

[2855] The following compound(s) was(were) obtained in a similar mannerto that of Example 566.

[2856] Example 567

[2857] tert-butyl(2-{4-[3-isobutoxy-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)carbamate

[2858] white powder

[2859] Mass (ESI+) : 482 (M+H)+

[2860] 200 MHz 1H NMR (CDCl3, d) : 1.03 (6H, d, J=6.7 Hz), 1.45 (9H,s),2.11 (1H,m),3.48-3.57 (2H,m), 3.79 (3H, s), 3.97-4.03 (2H, m), 4.97(1H, br), 5.88 (1H, s), 6.79 (2H, d, J=8.7 Hz), 6.82 (2H, d, J=8.9 Hz),7.09-7.19 (4H, m)

[2861] Example 568

[2862] tert-butyl(2-{4-[3-(2-methoxyethoxy)-1-(4-methoxy-phenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)carbamate

[2863] solid

[2864] Mass (ESI+) : 484 (M+H)+

[2865] 200 MHz 1H NMR (DMSO-d6, d) : 1.37 (9H, s), 3.22-3.32 (2H, m),3.31 (3H, s), 3.62-3.67 (2H, m), 3.75 (3H, s), 3.91-3.97 (2H, m),4.21-4.27 (2H, m), 6.04 (1H, s), 6.86-6.99 (5H, m), 7.10-7.15 (4H, m)

[2866] Example 569

[2867] tert-butyl(2-{4-[3-(2-ethoxyethoxy)-1-(4-methoxy-phenyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)carbamate

[2868] oil

[2869] Mass (ESI+) : 498 (M+H)+

[2870] 200 MHz 1H NMR (DMSO-d6, d) : 1.09-1.21 (3H, overlapping), 1.37(9H, s), 3.25-3.34 (2H, m), 3.66-3.71 (2H, m), 3.75 (3H, s), 3.90-4.15(4H, m), 4.21-4.26 (2H, m), 6.06 (1H, s), 6.86-6.96 (4H, m), 7.01 (1H,m), 7.12 (4H, d, J=8.9 Hz),

[2871] Example 570

[2872] tert-butyl (2-{4-[3-methoxy-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxylethyl)carbamate

[2873] powder

[2874] MS (ESI+) : m/z 441 (M+H)+

[2875] 200 MHz 1H NMR (CDCl3, d) : 1.45 (9H, s), 3.48-3.57 (2H, m), 3.92(3H, s), 3.97 (3H, s), 3.98-4.03 (2H, m), 4.99 (1H, br), 5.90 (1H, s),6.70 (1H, d, J=8.5 Hz), 6.82 (2H, d, J=8.9 Hz), 7.14 (2H, d, J=8.9 Hz),7.52 (1H, dd, J=2.5,8.5 Hz), 8.03 (1H, d, J=2.5 Hz)

[2876] Example 571

[2877] tert-butyl(2-{4-[3-ethoxy-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)carbamate

[2878] white powder

[2879] MS (ESI+) : m/z 455 (M+H)+

[2880] 200 MHz 1H NMR (DMSO-d6, d) : 1.33 (3H, t, J=7.0 Hz), 1.37 (9H,s), 3.22-3.33 (2H,m), 3.84 (3H,s), 3.92-3.98 (2H,m), 4.19 (2H, q), 6.08(1H, s), 6.85 (1H, d, J=8.8 Hz), 6.92 (2H, d, J=8.8 Hz), 7.02 (1H, t,J=5.5 Hz), 7.16 (2H, d, J=8.8 Hz), 7.58 (1H, dd, J=2.7, 8.8 Hz), 7.99(1H, d, J=2.7 Hz)

[2881] Example 572

[2882] tert-butyl[2-(4-{3-(difluoromethyl)-1-[4-(methyl-thio)phenyl]-1H-pyrazol-5-yl}phenoxy)ethyl]carbamate

[2883] MASS (ESI+): m/z =498.2 (M+Na).

[2884] 1HNMR (400 MHz, CDCl3): 1.45 (9H, s), 2.49 (3H, s), 3.54 2H, q, J=5.1 Hz), 4.02 (2H, t, J =5.1 Hz), 4.98 (1H, b.s) , 6.66 (1H, s) , 6.76(1H, t, J =55.1 Hz), 6.84 (2H, d, J =8.8 Hz), 7.15 (2H, d, J =8.8 Hz),7.2 (4H, s).

[2885] Example 573

[2886] tert-butyl(2-{4-[3-cyclopropyl-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)carbamate

[2887] oil

[2888] MS ESI+) : m/z 451 (M+H)

[2889] 1HNMR (200 MHz, CDCl3): 0.77-0.86 (2H, m), 0.93-1.04 (2H, m),1.45 (9H, s), 1.96-2.09 (1H, m), 3.48-3.57 (2H, m), 3.92 (3H, s),3.97-4.03 (2H, m), 4.97 (1H, brs), 6.10 (1H, s), 6.71 (1H, d, J =8.8Hz), 6.81 (2H, d, J =8.8 Hz), 7.11 (2H, d, J =8.8 Hz), 7.53 (1H, dd, J=2.7 ,8.8 Hz), 8.03 (1H, d, J =2.7 Hz)

[2890] Example 574

[2891] tert-butyl(2-{4-[3-(cyclopentyloxy)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)carbamate

[2892] oil

[2893] MS (ESI+) : m/z 494 (M+H)

[2894] 1HNMR (200 MHz, CDCl3): 1.45 (9H, s), 1.5 -1.99 (8H, m),3.48-3.57 (2H, m), 3.91 (3H, s), 3.98-4.04 (2H, m), 4.92 -5.05 (2H, m),5.88 (1H, s), 6.69 (1H, d, J=8.9 Hz), 6.82 (2H, d, J =8.8 Hz), 7.14 (2H,d, J =8.8 Hz), 7.52 1H, dd, J =2.7, 8.9 Hz), 8.02 (1H, d, J =2.7 Hz)

[2895] Example 575

[2896] tert-butyl(2-{4-[1-(4-methoxyphenyl)-3-(2,2,2-tri-fluoroethoxy)-1-H-pyrazol-5-yl]phenoxy}ethyl)carbamate

[2897] oil

[2898] MS (ESI+) : m/z 508 (M+H)

[2899] 1HNMR (200 MHz, CDCl3): 1.45 (9H, s), 3.48-3.57 (2H, m), 3.81(3H, s), 3.97-4.03 (2H, m), 4.62 (1H, d, J =8.5 Hz), 4.70 (1H, d, J =8.5Hz), 4.95 (1H, brs), 5.95 1H, s), 6.77-6.86 (4H, m), 7.08-7.18 (4H, m)

[2900] Example 576

[2901] tert-butyl(2-{4-[3-(2,2-difluoroethoxy)-1-(4-methoxy-phenyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)carbamate

[2902] oil

[2903] MS (ESI+) : m/z 490 (M+H)

[2904] 1HNMR (200 MHz, CDCl3): 1.45 (9H, s), 3.48-3.57 (2H, m), 3.80(3H, s), 3.97-4.03 (2H, m), 4.46 (2H, dt, J =4.3, 13.4 Hz), 4.96 (1H,brs), 5.91 (1H, s), 6.17 (1H, tt, J =4.3, 55.5 Hz), 6.77-6.88 (4H, m),7.09-7.18 (4H, m)

[2905] Example 577

[2906] tert-butyl(2-14-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1-H-pyrazol-5-yl]phenoxy}ethyl)-carbamate

[2907] oil

[2908] MS (ESI+) : m/z 509 (M+H)

[2909] 1HNMR (200 MHz, CDCl3) : 1.45 (9H, s), 3.48-3.57 (2H, m), 3.92(3H, s), 3.98-4.04 (2H, m), 4.61 (1H, d, J =8.4 Hz), 4.70 (1H, d, J =8.4Hz), 4.96 (1H, brs), 5.97 1H, s), 6.71 (1H, d, J=8.8 Hz), 6.83 (2H, d,J=8.8 Hz), 7.13 (2H, d, J =8.8 Hz), 7.48 (1H, dd, J =2.7 ,8.8 Hz), 8.02(1H, d, J =2.7 Hz)

[2910] Example 578

[2911] tert-butyl(2-{4-[3-(2,2-difluoroethoxy)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)-carbamate

[2912] solid

[2913] MS (ESI+) : m/z 513 (M+Na)

[2914] 1HNMR (200 MHz, CDC13) : 1.45 (9H, s), 3.48-3.57 (2H, m), 3.92(3H, s), 3.98-4.04 (2H, m), 4.46 (2H, dt, J =4.2 ,13.4 Hz), 4.96 (1H,brs), 5.94 (1H, s), 6.16 (1H, tt, J =4.2, 55.5 Hz), 6.71 (1H, d, J =8.8Hz), 6.83 (2H, d, J =8.9 Hz), 7.13 (2H, d, J =8.9 Hz), 7.48 (1H, dd, J=2.7 ,8.8 Hz), 8.02 (1H, d, J =2.7 Hz)

[2915] Example 579

[2916] tert-butyl(2-{4-[1-(4-methoxyphenyl)-4-methyl-1H-pyrazol-5-yl]phenoxy}ethyl)carbamate

[2917] oil

[2918] MS (ESI+) : m/z 424 (M+H)

[2919] 200 MHz 1H NMR (DMSO-d6, d) : 1.37 (9H, s), 2.01 (3H, s),3.23-3.33 (2H, m), 3.74 (3H, s), 3.92-3.98 (2H, m), 6.86-6.95 (4H, m),7.05-7.12 (4H, m), 7.55 (1H, s)

[2920] Example 580

[2921] tert-butyl(2-{4-[1-(6-methoxy-3-pyridinyl)-4-methyl-1H-pyrazol-5-yl]phenoxy}ethyl)carbamate

[2922] oil

[2923] MS (ESI+) : m/z 425 (M+H)

[2924] 1HNMR (400 MHz, CDCl3): 1.42 (9H, s), 2.09 (3H, s), 3.52-3.57(2H, m), 3.91 (3H, s), 4.01-4.04 (2H, m), 4.98 1H, brs), 6.68 (1H, d, J=8.8 Hz), 6.87 (2H, d, J =8.8 Hz), 7.08 (2H, d, J=8.8 Hz), 7.48 (1H, dd,J=2.7 ,8.8 Hz), 7.58 (1H, s), 8.00 (1H, d, J =2.7 Hz)

[2925] Example 581

[2926] tert-butyl(2-{4-[1-(4-methoxyphenyl)-3-(methylthio)-1-H-pyrazol-5-yl]phenoxy)ethyl)carbamate

[2927] oil

[2928] Mass (ESI+) : m/z 456 (M+H)

[2929] 1HNMR (200 MHz, CDCl3): 1.45 (9H, s), 2.58 (3H, s), 3.48-3.57(2H, m), 3.81 (3H, s), 3.97-4.03 (2H, m), 4.96 1H, m), 6.36 (1H, s),6.77-6.86 (4H, m), 7.12 (2H, d, J =8.9 Hz), 7.2 (2H, d, J =9.0 Hz)

[2930] Example 582

[2931] To a solution of(2-{4-[3-methoxy-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)aminehydrochloride (150 mg) and triethylamine (121 mg) in CH2Cl2 (3 mg) wasadded trifluoromethanesulfonic anhydride (113 mg). The mixture wasstirred at ambient temperature for 2 hours. Additional triethylamine (92mg) was added and stirring at ambient temperature was continued for 4hours. The mixture was concentrated in vacuo. The residue waspartitioned between AcOEt and 1M HCl. The organic layer was washed withsaturated aqueous sodium bicarbonate solution and saturated aqueoussodium chloride solution, dried over magnesium sulfate, and concentratedin vacuo. The residue was purified by silica gel column chromatographyeluted with AcOEt/n-hexane=50% to give1,1,1-trifluoro-N-(2-{4-[3-methoxy-1-(4-methoxy-phenyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)methane-sulfonamide(109 mg) as an oil.

[2932] IR (neat) : 2960, 1612, 1522 cm−1

[2933] Mass (ESI+) : 472 (M+H)+

[2934] 200 MHz 1H NMR (CDCl3, d) : 3.60-3.73 (2H, m), 3.80 (3H, s), 3.97(3H, s), 4.06-4.12 (2H, m), 5.45 (1H, brs), 5.89 (1H, s), 6.70-6.87 (4H,m), 7.15 (2H, d, J=8.9 Hz), 7.17 (2H, d, J=9.0 Hz)

[2935] Example 583

[2936] To a suspension of5-[4-(benzyloxy)phenyl]-3-hydroxy-1-(4-methoxyphenyl)-1H-pyrazole 2.0 gand K2CO3 2.23 g in DMSO 20 mg was added diethylsulfate 1.24 g. Afterstirring at ambient temperature for 2 hours, the reaction was quenchedby adding 28% aqueous ammonium hydroxide solution and ice. The mixturewas partitioned between AcOEt and H2O. The organic layer was washed withH2O and saturated aqueous sodium chloride solution, dried over magnesiumsulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography eluted with AcOEt/n-hexane =40% and thesolvent was evaporated in vacuo. The reisual solid was recrystallizedfrom IPE to give5-[4-(benzyloxy)phenyl]-3-ethoxy-1-(4-methoxy-phenyl)-1-H-pyrazole 1.44g as a powder.

[2937] Mass (ESI+) : 401 (M+H)+

[2938] 200 MHz 1H NMR (DMSO-d6, d) : 1.32 (3H, t, J=7.0 Hz), 3.76 (3H,s), 4.17 (2H, q, J=7.0 Hz), 5.08 (2H, s), 6.03 (1H, s), 6.92 (2H, d,J=9.0 Hz), 6.97 (2H, d, J=8.8 Hz), 7.09-7.16 (4H, m), 7.32-7.46 (5H, m)

[2939] The following compound(s) was(were) obtained in a similar mannerto that of Example 583.

[2940] Example 584

[2941]5-{5-[4-(benzyloxy)phenyl]-3-ethoxy-1H-pyrazol-1-yl}-2-methoxypyridineoil; MS (ESI+) : m/z 402 (M+H)+

[2942] 200 MHz 1H NMR (CDC13, d) : 1.43 (3H, t, J=7.1 Hz), 3.92 (3H, s),4.28 (2H, q, J=7.1 Hz), 5.05 (2H, s), 5.90 (1H, s), 6.70 (1H, d, J=8.7Hz), 6.91 (2H, d, J=8.8 Hz), 7.14 (2H, d, J=8.8 Hz), 7.35-7.43 (5H, m),7.51 (1H, dd, J=2.6,8.7 Hz), 8.04 (1H, d, J=2.6 Hz)

[2943] Example 585

[2944] To a solution of4-[3-ethoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenol (515.5 mg) in DMF(5 mg) was added sodium hydride 60% dispersion in mineral oil (79.7 mg)at 3° C. The mixture was stirred at ambient temperature for 40 minutes.To the rection mixture was added a solution of tert-butyl(2-bromoethyl)carbamate(558 mg) in DMF (2 mg). The mixture was stirredat at 60° C. for 24 hours. The reaction mixture was poured into icewater and was extracted with AcOEt. The organic layer was washed withsaturated aqueous sodium chloride solution, dried over magnesiumsulfate, and concentrated in vacuo. The residue was crystallized fromAcOEt, collected and washed with IPE to give 1st crop of tert-butyl(2-{4-[3-ethoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)carbamate(344 mg) as a white powder. The mother liqour was concentrated in vacuoand purified by silica gel column chromatography eluted withAcOEt/CHCl3=10% to give 2nd crop of tert-butyl(2-{4-[3-ethoxy-1-(4-methoxyphenyl)-1H-pyrazol-5-yl]phenoxy}ethyl)carbamate(218 mg ) as a powder.

[2945] Mass (ESI+) : 454 (M+H)+

[2946] 200 MHz 1H NMR (CDCl3, d) : 1.42 (3H, t, J=7.1 Hz), 1.45 (9H,s),3.48-3.57 (2H,m), 3.80 (3H, s), 3.97-4.03 (2H,m), 4.29 (2H, q, J=7.1Hz), 5.87 (1H, s), 6.79 (2H, d, J=9.0 Hz), 6.82 (2H, d, J=8.9 Hz),7.00-7.19 (4H, m)

[2947] Example 586

[2948] A suspension of5-[4-(benzyloxy)phenyl]-3-hydroxy-1-(4-methoxyphenyl)-1H-pyrazole (1.5g), 1-bromo-2-methylpropane (2.76 g) and anhydrous potassium carbonate(1.67 g) in DMF (10 ml) was added stirred at 100° C. for 1 hour. Themixture was poured into ice water and extracted with AcOEt. The organiclayer was washed with H2O, saturated aqueous sodium chloride solution,dried over magnesium sulfate, and concentrated invacuo. The residue waspurified by silica gel column chromatography eluted with AcOEt/n-hexane=30% to give5-[4-(benzyloxy)phenyl]-3-isobutoxy-1-(4-methoxyphenyl)-1H-pyrazole(1.64 g) as a solid.

[2949] powder

[2950] Mass (ESI+) : 42-9 (M+H)+

[2951] 200 MHz 1H NMR (CDCl3, d) : 1.03 (6H, d, J=6.6 Hz), 2.11 (1H, m),3.80 (3H, s), 3.99 (2H, d, J=6.6 Hz), 5.04 (2H, s), 5.88 (1H, s), 6.82(2H, d, J=9.0 Hz), 6.88 (2H, d, J=8.8 Hz), 7.11-7.20 (4H, m), 7.35-7.43(5H, m)

[2952] The following compound(s) was(were) obtained in a similar mannerto that of Example 586.

[2953] Example 587

[2954] 5-[4-(benzyloxy)phenyl]-3-(2-methoxyethoxy)-1(4-methoxyphenyl)-1-H-pyrazole

[2955] powder

[2956] Mass (ESI+) : 431 (M+H)+

[2957] 200 MHz 1H NMR (CDCl3, d) : 3.46 (3H, s), 3.73-3.80 (2H, m), 3.79(3H, s), 4.39-4.44 (2H, m), 5.04 (2H, s), 5.91 (1H, s), 6.83 (2H, d,J=8.9 Hz), 6.87 (2H, d, J=9.0 Hz), 7.10-7.20 (4H, m), 7.34-7.42 (5H, m)

[2958] Example 588

[2959]5-[4-(benzyloxy)phenyl]-3-(2-ethoxyethoxy)-1-(4-methoxyphenyl)-1-H-pyrazole

[2960] oil

[2961] Mass (ESI+) : 445 (M+H)+

[2962] 400 MHz 1H NMR (CDC13, d) : 1.25 (3H, t, J=7.0 Hz), 3.61 (2H, q,J=7.0 Hz), 3.79-3.82 (2H, m), 3.80 (3H, s), 4.39-4.42 (2H, mr), 5.04(2H, s), 5.91 (1H, s), 6.82 (2H, d, J=8.9 Hz), 6.88 (2H, d, J=8.7 Hz),7.12 (2H, d, J=8.7 Hz), 7.17 (2H, d, J=8.9 Hz), 7.36-7.41 (5H, m)

[2963] Example 589

[2964]2-{[5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-1H-pyrazol-3-yl]oxy}-N,N-dimethylacetamide

[2965] powder

[2966] Mass (ESI+) : 458 (M+H)+

[2967] 200 MHz1HNMR (DMSO-d6,d) :2.84 (3H,s),2.97 (3H,s),3.76 (3H, s),4.87 (2H, s), 5.09 (2H, s), 6.08 (1H, s), 6.92 (2H, d, J=9.0 Hz), 6.98(2H, d, J=8.8 Hz), 7.09-7.17 (4H, m), 7.34-7.43 (5H, m)

[2968] Example 590

[2969]5-[5-[4-(benzyloxy)phenyl]-3-(cyclopentyloxy)-1H-pyrazol-1-yl]-2-methoxypyridine

[2970] solid

[2971] MS (ESI+) : m/z 442 (M+H)

[2972] 1HNMR (200 MHz, CDCl3): 1.52-1.98 (8H, m), 3.92 (3H, s),4.98-5.05 (1H, m), 5.05 (2H, s), 5.88 (1H, s), 6.69 1H, d, J =8.7 Hz),6.91 (2H, d, J =8.8 Hz), 7.15 (2H, d, J =8.8 Hz), 7.35-7.43 (5H, m),7.52 (1H, dd, J =2.7 , 8.7 Hz), 8.04 (1H, d, J =2.7 Hz)

[2973] Example 591

[2974]5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-3-(2,2,2-trifluoroethoxy)-1-H-pyrazole

[2975] oil

[2976] MS (ESI+) : m/z 455 (M+H)

[2977] 1HNMR (200 MHz, DMSOd6): 3.76 3H, s), 4.81 (1H, d, J =9.0 Hz),4.90 (1H, d, J=9.0 Hz), 5.09 (2H, s), 6.21 (1H, s), 6.91-7.01 (4H, m),7.13- 7.19 (4H, m), 7.34-7.46 SH, m)

[2978] Example 592

[2979] 5-[4-(benzyloxy)phenyl]-3-(2,2-difluoroethoxy)l-1(4-methoxyphenyl)-1-H-pyrazole

[2980] oil

[2981] MS (ESI+) : m/z 437 (M+H)

[2982] 1HNMR (200 MHz, CDC13) : 3.80 (3H, s), 4.46 (2H, dt, J =4.2 ,13.5 Hz), 5.04 (2H, s), 5.91 (1H, s), 6.17 (1H, tt, J =4.2, 55.5 Hz),6.81-6.91 (4H, m), 7.10-7.19 (4H, m), 7.34-7.43 (5H, m)

[2983] Example 593

[2984]5-[5-[4-(benzyloxy)phenyl]-3-(2,2,2-trifluoroethoxy)-1-H-pyrazol-1-yl]-2-methoxypyridine

[2985] oil

[2986] Mass (ESI+) : 456 (M+H)

[2987] 1HNMR (200 MHz, CDCl3): 3.93 (3H, s), 4.61 (1H, d, J =8.4 Hz),4.69 (1H, d, J =8.4 Hz), 5.05 (2H, s), 5.97 (1H, s), 6.71 (1H, d, J =9Hz), 6.91 (2H, d, J =8.9 Hz), 7.14 (2H, d, J =8.9 Hz), 7.36-7.43 (5H,m), 7.48 (1H, dd, J =2.7 ,9 Hz), 8.04 (1H, d, J =2.7 Hz)

[2988] Example 594

[2989]5-[5-[4-(benzyloxy)phenyl]-3-(2,2-difluoroethoxy)-1H-pyrazol-1-yl]-2-methoxypyridine

[2990] oil

[2991] MS (ESI+) : m/z 438 (M+H)

[2992] 1HNMR (200 MHz, CDCl3) : 3.93 (3H, s), 4.46 (2H, dt, J =4.2 ,13.3Hz), 5.05 (2H, s), 5.94 (1H, s), 6.16 (1H, tt, J =4.2, 55.4 Hz), 6.71(1H, d, J =8.8 Hz), 6.91 (2H, d, J =8.8 Hz), 7.14 (2H, d, J =8.8 Hz),7.35-7.43 (5H, m), 7.48 (1H, dd, J =2.8 ,8.8 Hz), 8.04 (1H, d, J =2.8Hz)

[2993] Example 595

[2994] A suspension of5-{5-[4-(benzyloxy)phenyl]-3-hydroxy-1H-pyrazol-1-yl}-2-methoxypyridine(800 mg), dimethyl carbonate (0.9 mg) and potassium carbonate (888 mg)in DMF (8 mg) was stirredat 120° C. for 5 hours. The mixture was pouredinto ice water and extracted with AcOEt. The organic layer was washedwith H2O, saturated aqueous sodium chloride solution, dried overmagnesium sulfate, and concentrated in vacuo. The residue was purifiedby silica gel column chromatography eluted with AcOEt/n-hexane =30% togive5-{5-[4-(benzyloxy)phenyl]-3-methoxy-1-H-pyrazol-1-yl}-2-methoxy-pyridine(1.069 g) as a solid.

[2995] powder

[2996] MS (ESI+) : m/z 388 (M+H)+

[2997] 200 MHz1HNMR (CDCl3, d) : 3.92 (3H, s), 3.97 (3H, s), 5.05 (2H,s), 5.90 (1H, s), 6.71 (1H, d, J=8.7 Hz), 6.91 (2H, d, J=8.9 Hz), 7.14(2H, d, J=8.9 Hz), 7.35-7.43 (5H, m), 7.52 (1H, dd, J=2.6, 8.7 Hz), 8.05(1H, d, J=2.6 Hz)

[2998] Example 596

[2999] A solution of4,4,4-trifluoro-1-[4-(2-hydroxy-ethyl)phenyl]-1,3-butanedione (670 mg)and (4-nitrophenyl)hydrazine hydrochloride (439 mg) in AcOH (5 mg) andH2O (0.5 mg) was stirred at ambient temperature overnight. The mixturewas cocncentrated in vacuo, and the residue was partitioned betweenAcOEt and 1M HCl. The oreganic layer was washed with 1M HCl for twotimes, saturated aqueous sodium bicarbonate solution for three times,and saturated aqueous sodium chloride solution, dried over magnesiumsulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography eluted with AcOEt/n-hexane =10% and 15% togive2-{4-[1-(4-nitrophenyl)-3-(trifluoromethyl)-1-H-pyrazol-5-yl]phenyl}ethylacetate (501 mg) as an oil.

[3000] MS (ESI+) : m/z 420 (M+H)+, 442 (M+Na)+

[3001] 200 MHz 1H NMR (DMSO-d6, d) : 1.96 (3H, s), 2.91 (2H, t, J=6.8Hz), 4.22 (2H, t, J=6.8 Hz), 7.22-7.37 (5H, m), 7.61 (2H, d, J=9.0 Hz),8.30 (2H, d, J=9.0 Hz)

[3002] The following compound(s) was(were) obtained in a similar mannerto that of Example 596.

[3003] Example 597

[3004]5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-4-methyl-3-(trifluoromethyl)-1-H-pyrazole

[3005] MASS (ESI+): m/z =439.1 (M+l), 461.2 (M+Na).

[3006] 1HNMR (400 MHz, CDCl3): 2.15 (3H, s), 3.79 (3H, s), 5.06 (2H, s),6.8 (2H, d, J=8.9 Hz), 6.95 (2H, d, J =8.7 Hz), 7.07 (2H, d, J =8.7 Hz),7.14 (2H, d, J =8.9 Hz), 7.342-7.44 (5H, m).

[3007] Example 598

[3008]2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenyl}ethylacetate

[3009] MASS (ESI+): m/z =346.1 (M-Ac+2), 388.1 (M+1). 1HNMR (400 MHz,CDC13): 2.04 (3H, s), 2.94 (2H, t, J =7 Hz), 3.94 (3H, s), 4.28 (2H, t,J =7 Hz), 6.72 (1H, s), 6.77 (1H, t, J =55 Hz), 6.75 (1H, d, J =8.8 Hz),7.17 (2H, d, J =8.5 Hz), 7.22 (2H, d, J =8.5 Hz), 7.54 (1H, dd, J =3.9,8.8 Hz), 8.08 (1H, d, J =3.9 Hz)

[3010] Example 599

[3011] To a solution of ammonium chloride 58.8 mg in H2O 0.5 mg wasadded iron powder 368 mg and EtOH 2 mg. The reaction mixture was warmedin oil bath, and a solution of2-{4-[l-(4-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]phenyl}ethylacetate 460.7 mg in EtOH 3 mg was added. After being refluxed for 3hours, the reaction mixture was cooled to ambient temperature andunsoluble matter was removed by filtration. The filtrate wasconcentrated in vacuo. The residue was dissolved in AcOEt, and washedwith saturated aqueous sodium bicarbonate solution and saturated aqueoussodium chloride solution, dried over magnesium sulfate, and concentratedin vacuo. The residue was recrystallized from IPE to give2-{4-[1-(4-aminophenyl)-3-(trifluoro-methyl)-1-H-pyrazol-5-yl]phenyl}ethylacetate 182.3 mg as a powder.

[3012] MS (ESI+) : m/z 390 (M+H)+

[3013] 200 MHz 1H NMR (DMSO-d6, d) : 1.96 (3H, s), 2.87 (2H, t, J=6.8Hz), 4.20 (2H, t, J=6.8 Hz), 5.46 (2H, s), 6.54 (2H, d, J=8.7 Hz), 6.95(2H, d, J=8.7 Hz), 7.07 (1H, s), 7.18-7.28 (4H, m)

[3014] Example 600

[3015] A mixture of 2-{4-[1-(4-aminophenyl)-3-(trifluoro-methyl)-1-H-pyrazol-5-yl]phenyl}ethyl acetate 165.6 mg and 2,5-dimethoxytetrahydrofuran 112 mg in AcOH 3 mg was stirred at 50° C. for3 hours. 2,5-Dimethoxytetrahydrofuran 0.22 mg was added and the mixturewas stirred at 50° C. for 2 hours. The mixture was partitioned betweenethyl acetate and H2O. The organic layer was washed with saturatedaqueous sodium bicarbonate solution and saturated aqueous sodiumchloride solution, dried over magnesium sulfate, and concentrated invacuo. The residue was purified by preparative thin layer silica gelchromatography developed by AcOEt/n-hexane =20%. The seaparated silicagel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated invacuo to give2-{4-[1-[4-(1-H-pyrrol-1-yl)phenyl]-3-(trifluoromethyl)-1-H-pyrazol-5-yl]phenyllethylacetate 136.1 mg as an oil.

[3016] MS (ESI+) : m/z 440 (M+H)+

[3017] 200 MHz 1H NMR (DMSO-d6, d) : 1.95 (3H, s), 2.88 (2H, t, J=6.8Hz), 4.20 (2H, t, J=6.8 Hz), 6.29 (2H, t, J=2.0 Hz), 7.18 (1H, s),7.23-7.32 (4H, m), 7.39-7.47 (4H, m), 7.69 (2H, d, J=8.8 Hz)

[3018] Example 601

[3019] 1M NaOH (436 μl) was added to a solution of2-(4-[1-[4-(1-H-pyrrol-1-yl)phenyl]-3-(trifluoromethyl)-1-H-pyrazol-5-yl]phenyl}ethylacetate (128 mg) in THF (1.5 mg) and MeOH (0.3 mg) under ice bathcooling. The mixture was stirred at 0° C. ambient temperature for 2hours. The mixture was neutralized with 1M HCl (436 μl), and waspartitioned between AcOEt and H2O. The organic layer was washed withsaturated aqueous sodium chloride solution, dried over magnesiumsulfate, and concentrated in vacuo. The residue was purified bypreparative thin layer silica gel chromatography developed byAcOEt/n-hexane =50%. The seaparated silica gel was extracted with 10%MeOH/CHCl3 and the solvent was evaporated in vacuo to give2-{4-[1-[4-(1-H-pyrrol-1-yl)phenyl]-3-(trifluoromethyl)-1-H-pyrazol-5-yl]phenyl}ethanol(96.5 mg) as an amorphous powder.

[3020] IR (KBr) : 3404, 2924, 2883, 1612, 1522 cm−1

[3021] MS (ESI+) : m/z 398 (M+H)+

[3022] 200 MHz 1HNMR (DMSO-d6, d) : 2.67-2.75 (2H, m) , 3.55-3.65 (2H,m), 4.64 (1H, t, J=5.1 Hz), 6.30 (2H, t, J=2.0 Hz), 7.16 (1H, s),7.19-7.28 (4H, m), 7.40-7.48 (4H, m), 7.70 (2H, d, J-8.9 Hz)

[3023] Example 602

[3024] A mixture of 10% Pd-C 50% wet (100 mg) and ethyl5-(4-cyanophenyl)-1-(4-methoxyphenyl)-1-H-pyrazole-3-carboxylate (1 g)in THF (10 ml), MeOH (5 mg), and 1M HCl (2.9 mg) was hydrogenated underH2 latm at ambient temperature for 6.5 hours. The catalyst was filteredoff through a celite pad and the pad was washed with MeOH. The filtrateand combined washings were concentrated in vacuo. The residue wasdissolved in EtOH and concentrated in vacuo. The residue wascrystallized from AcOEt to give ethyl5-[4-(aminomethyl)phenyl]-1-(4-methoxyphenyl)-1-H-pyrazole-3-carboxylatehydrochloride (984 mg) as a powder.

[3025] MS (ESI+) : m/z 352 (M+H)+

[3026] 1HNMR (DMSO-d6) 51.32 (3H, t, J=7.1 Hz), 3.80 (3H, s), 4.01 (2H,s), 4.33 (2H, q, J=7.1 Hz), 7.00 (2H, d, J=9.0 Hz), 7.14 (1H, s), 7.28(2H, d, J=9.0 Hz), 7.31 (2H, d, J=8.3 Hz), 7.47 (2H, d, J=8.3 Hz), 8.30(2H, brs)

[3027] The following compound(s) was(were) obtained in a similar mannerto that of Example 602.

[3028] Example 603

[3029] ethyl5-[4-(aminomethyl)phenyl]-1-(6-methoxy-3-pyridinyl)-1-H-pyrazole-3-carboxylatedihydrochloride

[3030] powder

[3031] MS (ESI+) : m/z 353 (M+H)

[3032] 1HNMR (200 MHz, DMSOd6): 1.32 (3H, t, J =7.1 Hz), 3.88 (3H, s),3.97-4.06 (2H, m), 4.34 (2H, q, J =7.1 Hz), 6.94 (1H, d, J 8.7 Hz), 7.17(1H, s), 7.35 (2H, d, J =8.2 Hz), 7.51 (2H, d, J =8.2 Hz), 7.78 (1H, dd,J =2.7 ,8.7 Hz), 8.15 (1H, d, J =2.7 Hz), 8.47 (2H, brs)

[3033] Example 604

[3034] {4-[3-methoxy-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]-benzyl}aminehydrochloride

[3035] oil

[3036] MS (ESI+) : m/z 310 (M+H)

[3037] 1HNMR (200 MHz, DMSOd6): 3.76 (3H, s), 3.85 (3H, s), 3.91-4.26(2H, m), 6.16 (1H, s), 6.93 (2H, d, J =8.9 Hz), 7.16 (2H, d, J =8.9 Hz),7.26 (2H, d, J =8.2 Hz), 7.45 2H, d, J =8.2 Hz), 8.41 (2H, brs)

[3038] Example 605

[3039]{4-[3-isopropoxy-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]benzyl}aminehydrochloride

[3040] powder

[3041] MS (ESI+) : m/z 338 (M+H)

[3042] 1HNMR (200 MHz, DMSOd6): 1.32 (6H, d, J =6.2 Hz), 3.76 (3H, s),4.00 (2H, s), 4.77 (1H, m), 6.11 (1H, s), 6.93 (2H, d, J =8.9 Hz), 7.15(2H, d, J =8.9 Hz), 7.25 (2H, d, J =8.2 Hz), 7.44 (2H, d, J =8.2 Hz),8.31 (2H, brs)

[3043] Example 606

[3044] Et3N (326 mg) and then a solution of di-tert-butyl dicarbonate(594 mg) in CH2Cl2 (3 mg) was added successively to a suspension ofethyl5-[4-(aminomethyl)phenyl]-1-(4-methoxyphenyl)-1-H-pyrazole-3-carboxylatehydrochloride (960 mg) in CH2Cl2 (9 mg). After stirring at ambienttemperature for 1 hour, the reaction mixture was concentrated in vacuo.The residue was partitioned between ethyl acetate and 1M HCl. Theorganic layer was washed with saturated aqueous sodium bicarbonatesolution and saturated aqueous sodium chloride solution, dried overmagnesium sulfate, and concentrated in vacuo. The residue wasrecrystallized from AcOEt/n-hexane to give ethyl5-(4-{[(tert-butoxy-carbonyl)amino]methyl}phenyl)-1-(4-methoxyphenyl)-1-H-pyrazole-3-carboxylate(1.045 g) as a powder.

[3045] MS (ESI+) : m/z 452 (M+H)+

[3046] 1HNMR (DMSO-d6) 51.31 (3H, t, J=7.1 Hz), 1.38 (9H, s), 3.79 (3H,s), 4.11 (2H, d, J=6.2 Hz), 4.32 (2H, q, J=7.1 Hz), 6.99 (2H, d, J=8.9Hz), 7.07 (1H, s), 7.20 (4H, s), 7.26 (2H, d, J=8.9 Hz), 7.40 (1H, t,J=6.2 Hz)

[3047] The following compound(s) was(were) obtained in a similar mannerto that of Example 606.

[3048] Example 607

[3049] ethyl5-(4-{[(tert-butoxycarbonyl)amino]methyl}phenyl)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazole-3-carboxylate

[3050] powder

[3051] Mass (ESI+) : m/z 453 (M+H)

[3052] 1HNMR (200 MHz, DMSOd6): 1.32 (3H, t, J =7.1 Hz), 1.38 (9H, s),3.88 (3H, s), 4.12 (2H, d, J =6.1 Hz), 4.33 (2H, q, J =7.1 Hz), 6.92(1H, d, J =8.9 Hz), 7.10 (1H, s), 7.19-7.28 (4H, m), 7.41 (1H, t, J =6.0Hz), 7.74 (1H, dd, J =2.7 ,8.9 Hz), 8.14 (1H, d, J =2.7 Hz)

[3053] Example 608

[3054] A mixture of ethyl5-(4-{[(tert-butoxycarbonyl)amino]-methyl}phenyl)-1-(4-methoxyphenyl)-1-H-pyrazole-3-carboxylate(500 mg) and sodium methoxide (239 mg) in formamide 5 mg was stirred at70° C. for 2 hours. The mixture was cooled to ambient temperature andpartitioned between AcOEtand brine. The organic layer was washed withsaturated aqueous sodium chloride solution, dried over magnesiumsulfate, and concentrated in vacuo to give tert-butyl{4-[3-(aminocarbonyl)-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]benzyl}carbamate(512 mg) as an oil.

[3055] MS (ESI+) : m/z 423 (M+H)+

[3056] 1H NMR (DMSO-d6) 5 1.38 (9H, s), 3.78 (3H, s), 4.11 (2H, d,J=6.IHz), 6.93 (1H, s), 6.98 (2H,d, J=8.9 Hz), 7.19-7.43 (8H, m), 7.64(1H, brs)

[3057] Example 609

[3058] Phosphorous oxychloride (0.22 mg) was addedto DMF (2 mg) underice bath cooling. To this solution was added a solution of tert-butyl{4-[3-(aminocarbonyl)-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]benzyl}carbamate (499 mg) in DMF (3 mg) dropwise. Thereaction mixture was stirred at 4° C. for 1 hour. Phosphorousoxychloride (0.15 mg) was added and the reaction mixture was stirred at4° C. for 1 hour. The reaction was quenched by adding saturated aqueoussodium bicarbonate solution. The mixture was extracted with ethylacetate. The organic layer was washed with saturated aqueous sodiumchloride solution, dried over magnesium sulfate, and concentrated invacuo. The residue was purified by preparative thin layer silica gelchromatography developed by AcOEt/n-hexane=40%. The seaparated silicagel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated invacuo to give tert-butyl{4-[3-cyano-1-(4-methoxy-phenyl)-1-H-pyrazol-5-yl]benzylcarbamate (136mg) as an oil. MS (ESI+) : m/z 427 (M+Na)+, (ESI−) : m/z 403 (M-H)+200MHz1HNMR (CDCl3, d) :1.46 (9H, s), 3.83 (3H, s), 4.32 (2H, d, J=5.9 Hz),4.75 (1H, br), 6.83 (1H, s), 6.87 (2H, d, J=9.0 Hz), 7.11-7.26 (6H, m)

[3059] Example 610

[3060] To a solution of5-[4-(2-{[tert-butyl(dimethyl)-silyl]oxy}ethoxy)phenyl]-1-(4-methoxyphenyl)-4-methyl-3-(trifluoromethyl)-1-H-pyrazole(5.2 g) in EtOH (200 mg) was added conc.HCl (20 mg) at room temperature.After stirring for 2 hrs, the reaction mixture was partitioned betweenEtOAc and water. Organic layer was separated and washed with water,dried over MgSO4, filtered and evaporated. The residue waschromatographed on silica gel (Hex/EtOAc=2:1 -1:1) to give 2.05 g (51%)of2-{4-[1-(4-methoxyphenyl)-4-methyl-3-(trifluoromethyl)-1-H-pyrazol-5-yl]phenoxylethanolas a crystal.

[3061] MASS (ESI+): e/z =415.1 (M+Na).

[3062] 1HNMR (400 MHz, CDCl3): 2.15 (3H, s), 1.99 (1H, t, J =6.2 Hz),2.15 (3H, s), 3.95-4.00 (2H, m), 4.08-4.10 (2H, m) , 6.80 (2H, d, J =9Hz), 6.90 (2H, d, J =8.8 Hz) ) 7.08 (2H, d, J =8.8 Hz), 7.13 (2H, d, J=9 Hz) )

[3063] Example 611

[3064] To solution of4-[1-[4-(methylthio)phenyl]-3-(tri-fluoromethyl)-1-H-pyrazol-5yl]phenol(5.0 g) in DMF(20 mg) was added NaH (0.75 g) over 25 min under icecooling (5-20° C.) (gas), stir at 3° C. for 10 min. tert-ButylN-(2-bromoethyl)carbamate (4.48 g) in DMF (5 mg) was added to themixture over 10 min stir at 60° C. (bath 70° C.) for 6h and allowed tostand for overnight.

[3065] The mixture was poured into water (50 mg) and EtOAc (30 mg),seperation and extracted with EtOAc (10 ml). The organic layer waswashed with water (25×3) and brine (25 mg), dried MgSO4, evaporated. Theresidue was column chromatographed on silica gel (75 mg, 15v/w,AcOEt/Hex(2:1-1:1) and evaporated to give 7.0 g of tert-butyl(2-{4-[1-[4-(methyl-thio)phenyl]-3-(trifluoromethyl)-1-H-pyrazol-5-yl]-phenoxy}ethyl)carbamateas an oil.

[3066] MASS (ESI+): m/z =516.1 (M+Na).

[3067] 1HNMR (400 MHz, CDCl3) : 1.45 (9H, s) , 2.49 (3H, s), 3.49-3.58(2H, m), 4.02 (2H, t, J=10.2 Hz), 4.97 (1H, b.s), 6.68 (1H, s), 6.84(2H, d, J =17.5 Hz), 7.14 (2H, d, J =17.5 Hz), 7.21 (4H, s).

[3068] The following compound(s) was(were) obtained in a similar mannerto that of Example 611.

[3069] Example 612

[3070] tert-butyl(2-{4-[1-(4-methoxyphenyl)-4-methyl-3-(trifluoromethyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)-carbamate

[3071] MASS (ESI+): m/z =514.2 (M+Na).

[3072] 1HNMR (400 MHz, CDCl3): 1.45 (9H, s), 2.15 (3H, s), 3.52-3.56(2H, m), 3.79 (3H, s), 4.02 (2H, t, J =5.1 Hz), 4.99 (1H, b.s), 6.80(2H, d, J =9.0 Hz), 6.87 (2H, d, J =8.8 Hz), 7.07 (2H, d, J =8.8 Hz),7.13 ( H, d, J =9.0 Hz)

[3073] Example 613

[3074] To a suspension of(2-{4-[1-[4-(methylthio)phenyl]-3-(trifluoromethyl)-1-H-pyrazol-5-yl]phenoxylethyl)aminehydrochloride (7.5 g) in H2O (150 mg) and EtOH (75 mg) was added NaOCN(2.27 g) at room temperature. pH was ajusted to 6.3 with 1NHCl . Themixture was stirred for 5 hours under the condition of pH 6.0-7.0. Thereaction mixture was extracted with EtOAc and washed with dil. NaCl(twice), dried over MgSO4, filtered and evaporated. The residue wascolumn chromatographed on silica gel (CH2Cl2/MeOH) an devaporated. Theresidue was crytalized from IPE/EtOH. Recrystalized from EtOH/H2O (50mg-50 mg Final) and dried to give 4.10 g (54%) ofN-(2-14-[1-[4-(methylthio)phenyl]-3-(trifluoro-methyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)urea.

[3075] MASS (ESI+): m/z =459.1 (m+Na)

[3076] 1HNMR (400 MHz, DMSOd6) : 2.05 (3H, s), 3.33 (2H, q, J =5.6 Hz),3.95 (2H, t, J =5.6 Hz), 5.54 (2H, b.s), 6.16 (1H, t, J =5.6 Hz), 6.96(2H, d, J =8.8 Hz), 7.09 (1H, s), 7.22 (2H, d, J =8.6 Hz), 7.27 (2H, d,J =8.7 Hz), 7.32 (2H, d, J =8.7 Hz)

[3077] HORIBA FT-IR for Windows Ver. 4.08 (cm−1):3399.89, 3197.40,1650.77, 1614.13, 1554.34, 1475.28, 1459.85,1442.49, 1232.29, 1160.94,1126.22, 1087.66, 1049.09, 970.019, 827.312.

[3078] The following compound(s) was (were) obtained in a similar mannerto that of Example 613.

[3079] Example 614

[3080]N-(2-{4-[1-(4-methoxyphenyl)-4-methyl-3-(trifluoro-methyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)urea

[3081] mp: 150.5-151.1° C.

[3082] MASS (ESI+): m/z =457.2 (m+Na).

[3083] 1HNMR (400 MHz, CDC13): 2.15 (3H, s), 3.6 (2H, dt, J =5 ,5.4 Hz),3.78 (3H, s), 4.04 (2H, t, J =5 Hz), 4.5 (2H, b.s), 5.08 (1H, t, J =5.4Hz), 6.8 (2H, d, J =9 Hz), 6.86 (2H, d, J =8.8 Hz), 7.07 (2H, d, J =8.8Hz), 7.13 (2H, d, J =9 Hz)

[3084] Example 615

[3085]N-[2-(4-{3-(difluoromethyl)-1-[4-(methylthio)phenyl]-1-H-pyrazol-5-yl}phenoxy)ethyl]urea

[3086] mp: 184.3-184.7° C.

[3087] MASS (ESI+): m/z =441.1 (M+Na).

[3088] 1HNMR (400 MHz, DMSOd6): 2.5 (3H, s) , 3.33 (2H, dt, J =5.6 ,6.3Hz), 3.95 (2H, t, J =5.6 Hz), 5.53 (2H, b.s), 6.15 (1H, t, J =6.3 Hz),6.85 (1H, s), 6.95 (2H, d, J =8.7 Hz), 7.09 1H, t, J=54.1 Hz), 7.2 (2H,d, J=8.7 Hz), 7.23 (2H, d, J =8.7 Hz), 7.3 (2H, d, J =8.7 Hz)

[3089] Example 616

[3090]N-(2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenyl}ethyl)urea

[3091] mp: 194-196 ° C.

[3092] MASS (ESI+): m/z =410.2 (M+Na)

[3093] 1HNMR (400 MHz, DMSOd6): 2.68 (2H, t, J =7.3 Hz), 3.19 (2H, dt, J=5.6 ,7.3 Hz)) 3.88 (3H, s) , 5.42 (2H, b.s), 5.95 (1H, t, J =5.6 Hz),6.91 (1H, d, J =8.8 Hz), 6.93 (1H, s), 7.11 (1H, t, J =54.4 Hz), 7.23(4H, s), 7.7 (1H, dd, J =2.8 ,8.8 Hz), 8.15 (1H, d, J =2.8 Hz) ).

[3094] Example 617

[3095] N-{4-[1-(6-methoxy-3-pyridinyl)-3-(trifluoromethyl)-1-H-pyrazol-5-yl]benzyl}urea

[3096] Crystal. mp: 147-149° C.

[3097] MASS (ESI+): m/z =414.1 (M+Na).

[3098] 1HNMR (400 MHz, CDCl3): 3.93 (3H, s), 4.37 (2H, d, J =6 Hz), 4.52(2H, b.s), 5.08 (1H, t, J =6 Hz), 6.73 (1H, s), 6.77 (1H, d, J =8.8 Hz),7.18 (2H, d, J =8.3 Hz), 7.27 (2H, d, J =8.3 Hz), 7.59 (1H, dd, J =2.7,8.8 Hz), 8.03 (1H, d, J =2.7 Hz)

[3099] Example 618

[3100]N-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]benzyl}urea

[3101] MASS (ESI+): m/z =396.1 (m+Na).

[3102] 1HNMR (400 MHz, DMSOd6): 3.87 (3H, s), 4.17 (2H, d, J =6 Hz),5.55 (2H, b.s), 6.45 (1H, t, J =6 Hz), 6.91 (1H, d, J =8.8 Hz), 6.94(1H, s), 7.11 (1H, t, J =53.2 Hz), 7.27 (4H, s), 7.71 (1H, dd, J =2.7,8.8 Hz), 8.14 (1H, d, J =2.7 Hz) ).

[3103] Example 619

[3104] A mixture ofN-(2-{4-[1-[4-(methylthio)phenyl]-3-(tri-fluoromethyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)urea(250 mg) and mCPBA (326 mg) in CH2Cl2 (10 ml)was stirred for 18 hrs.sat. NaHCO3 and CH2Cl2 was added. Aqueou layer was separated andextracted. The combined organic layer was washed with sat. NaHCO3(twice), dried and evaporated to give 207 mg (79.9%) of crude product.The crude product was column chromatographed by preparative TLC to give207 mg (80%) ofN-(2-{4-[1-[4-(methylsulfinyl)phenyl]-3-(trifluoromethyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)ureaas an amorphous.

[3105] MASS (ESI+): 475.1 (m+Na).

[3106] 1HNMR (400 MHz, DMSOd6) : 2.79 (3H, s), 3.3-3.34 (2H, m), 3.95(2H, t, J =5.6 Hz), 5.53 (2H, b.s), 6.15 (1H, t, J 5.6 Hz), 6.97 (2H, d,J 8.8 Hz), 7.16 (1H, s), 7.23 (2H, d, J =8.8 Hz), 7.55 (2H, d, J =8.6Hz), 7.77 (2H, d, J =8.6 Hz)

[3107] Example 620

[3108] A mixture ofN-(2-{4-[1-[4-(methylthio)phenyl]-3-(tri-fluoromethyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)urea(250 mg) and mCPBA (326 mg) in CH2Cl2 (10 mg)was stirred for 18 hrs.sat. NaHCO3 and CH2Cl2 was added. Aqueou layer was separated andextracted. The combined organic layer was washed with sat. NaHCO3(twice), dried and evaporated to give 207 mg (79.9%) of crude product.The crude product was column chromatographed by preparative TLC to give116 mg (43%) ofN-(2-{4-[1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)ureaas a amorphous.

[3109] MASS (ESI+): m/z =491.0 (m+Na).

[3110] 1HNMR (400 MHz, DMSOd6): 3.28 (3H, s) , 3.28-3.34 (2H, m), 3.96(2H, t, J =5.4 Hz), 5.54 (2H, b.s), 6.16 (1H, t, J =5.4 Hz), 6.99 (2H,d, J =8.4 Hz), 7.18 (1H, s), 7.25 (2H, d, J =8.4 Hz), 7.61 (2H, d, J=8.4 Hz), 8.01 (2H, d, J =8.4 Hz)

[3111] Example 621

[3112] To a solution of2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenyl}ethylacetate (10 g) in THF (120 mg) and MeOH (30 mg) was added lNNaOH (60 mg)at room temperature. The reaction mixture was stirred at the sametemperature for 4 hrs, and then neutralized with 1NHCl (60 mg),evaporated, and extracted twice with EtOAc. The organic layer was washedwith water and brine, dried over MgSO4, filtered and evaporated to givecrude product. The residue was column chromatographed on silica gel andcrystalized from IPE and filtered to give 3.0 g of2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenyl}ethanol.The filtrate was evaporated and filtered to give 4.65 g of secondcrystal.

[3113] MASS (ESI+): m/z =368.2 (M+Na).

[3114] 1HNMR (400 MHz, CDCl3): 1.49 (1H, t, J =5.8 Hz), 2.87 (2H, t, J=6.5 Hz), 3.88 (2H, dt, J =5.8 ,6.5 Hz), 6.71 (1H, s), 6.76 (1H, t, J=55 Hz), 6.75 (1H, d, J =8.8 Hz), 7.17 (2H, d, J=8.4 Hz), 7.21 (2H, d, J=8.4 Hz), 7.55 1H, dd, J =2.8 ,8.8 Hz), 8.08 (1H, d, J =2.8 Hz)

[3115] Example 622

[3116] To a solution of2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenyl}ethanol(7.4 g) and Et3N(4.5 mg) in CH2Cl2 (75 mg) was added MsCl (2.5 mg) underice-cooling. After stirring for 1 hour, the reaction mixture wasquenched with water, separated. The aqueous layer was extracted withCH2Cl2 and combined organic layer was washed with water and brine, driedover MgSO4, filtered and evaporated under reduced pressure to give 10.5g (quant) of2-{4-[3-(difluoromethyl)-l-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenyl}ethylmethanesulfonate as an oil.

[3117] MASS (ESI+): m/z =446.1 (M+Na).

[3118] 1HNMR (400 MHz, CDCl3) :2.9 (3H, s), 3.06 (2H, t, J=6.8 Hz), 3.94(3H, s), 4.42 (2H, t, J =6.8 Hz), 6.73 (1H, s), 6.76 (1H, d, J =8.8 Hz),6.77 (1H, t, J =55 Hz), 7.19 (2H, d, J =8.6 Hz), 7.23 (2H, d, J =8.6Hz), 7.55 (1H, dd, J =2.6 ,8.8 Hz), 8.04 (1H, d, J =2.6 Hz) )

[3119] Example 623

[3120] A mixture of2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenyl}ethylmethanesulfonate (7.4 g) and Ph(CO)2NK (3.88 g) in DMF (50 mg) wasstirred at 60° C. for 8 hours. Added water. The organic layer wasextracted twice with EtOAc. Aqueous layer was washed with water (twice)and brine, dried over MgSO4, filtered, and evaporated under reducedpressure. The residue was triturated with IPE, filtered and dried togive 7.65 g of2-(2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenyllethyl)-1-H-isoindole-1,3(2H)-dione as a solid.

[3121] MASS (ESI+): 475.2 (M+l), 497.2 (M+Na).

[3122] 1HNMR (400 MHz, CDCl3): 3 (2H, t, J =7.6 Hz), 3.92 (2H, t, J =7.6Hz), 3.95 (3H, s), 6.7 (1H, s), 6.73 (1H, d, J =8.8 Hz), 6.76 (1H, t, J=55 Hz), 7.14 (2H, d, J =8.1 Hz), 7.22 (2H, d, J=8.1 Hz)) ,7.46 (1H, dd,J=2.7 ,8.8 Hz), 7.71-7.73 (2H, m), 7.83-7.85 (2H, m), 8.1 (1H, d, J =2.7Hz).

[3123] Example 624

[3124] A mixture of 2- (2-{4- [3- (difluoromethyl) -1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenyl}ethyl)-1-H-isoindole-1,3(2H)-dion (5.0 g) and NH2NH2 (2.8 mg) in CH3CN (50 mg) was stirred at60° C. for 8 hours. The reaction mixture was filtered. Filtrate wasevaporated under reduced pressure. 4N HCl/Dioxane and then IPE wasadded. The product was triturated, filtered and died under reducedpressure to give 3.94 g (90%) of(2-{4-[3-(difluoromethyl)-l-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenyl}ethyl)aminedihydrochloride as a solid.

[3125] MASS (ESI+): m/z =345.2 (M(free)+1).

[3126] 1HNMR (400 MHz, DMSOd6) : 2.9-2.95 (2H, m), 3.01-3.06 (2H, m),3.88 (3H, s), 6.92 (1H, d, J =8.8 Hz), 6.95 (1H, s), 7.13 (1H, t, J=56.1Hz), 7.27 (2H, d, J=8.4 Hz), 7.3 (2H, d, J =8.4 Hz), 7.72 (1H, dd, J=2.8 ,8.8 Hz), 8.15 (1H, d, J =2.8 Hz).

[3127] The following compound(s) was(were) obtained in a similar mannerto that of Example 602.

[3128] Example 625

[3129]{4-[1-(6-methoxy-3-pyridinyl)-3-(trifluoromethyl)-1-H-pyrazol-5-yl]benzyl}aminedihydrochloride

[3130] MASS (ESI+): m/z =332.2 (M-NH2), 349.1 (M+H). 1HNMR (400 MHz,DMSOd6) : 3.88 (3H, s), 6.94 (1H, d, J =9.6 Hz), 7.25 (1H, s), 7.37 (2H,d, J =8 Hz), 7.53 (2H, d, J =8 Hz), 7.8 (1H, dd, J =2.9 ,9.6 Hz), 8.45(1H, d, J =2.8 Hz).

[3131] Example 626

[3132]{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]-benzyl}aminehydrochloride

[3133] MASS (ESI+): m/z =314.2 (M-NH2), 331.1 (M+1). 1HNMR (400 MHz,DMSOd6): 3.88 (3H, s), 6.93 (1H, d, J =8.8 Hz), 7 .00 (1H, s) , 7.14(1H, t, J =54 Hz), 7.35 (2H, d, J =8.2 Hz), 7.53 (2H, d, J =8.2 Hz),7.75 (1H, dd, J =2.7 ,8.8 Hz), 8.15 (1H, d, J =2.7 Hz) )

[3134] Example 627

[3135] To a solution of 5-hydrazino-2-methoxypyridine dihydrochloride(4.78 g) and Et3N (7.01 g) in EtOH (50 mg) was added{(2R,3S)-3-[4-(benzyloxy)phenyl]-2-oxiranyl)-(cyclopropyl)methanone(5.10 g) and refluxed for 9 hours. THs mixture was concentrated invacuo. To the residue were added AcOEt and 1MHCl, and unsoluble matterwas filtered off through a celit pad. The filtrate was partitioned, andthe organic lauer was washed with saturated aqueous sodium bicarbonatesolution, dried over magnesium sulfate, and concentrated in vacuo. Theresidue was dissolved in CH2Cl2 (50 mg). To this solution were addedEt3N (5.26 g) and methanesulfonyl chloride (2.98 g) successively underice-bath cooling. The mixture was stirred at ambient temperature for 2hours. The mixture was washed with 1M HCl, saturated aqueous sodiumbicarbonate solution, and saturated aqueous sodium chloride solution,dried over magnesium sulfate, and concentrated in vacuo. The residue waspurified by silica gel column chromatography eluted withAcOEt/n-hexane=20% to give5-15-[4-(benzyloxy)phenyl]-3-cyclopropyl-1-H-pyrazol-1-yl}-2-methoxypyridine(4.20 g) as a solid.

[3136] MS (ESI+) : m/z 398 (M+H)

[3137] 1HNMR (200 MHz, DMSOd6): 0.69 -0.78 (2H, m), 0.87 -0.97 (2H, m),1.89-1.99 (1H, m), 3.85 (3H, s), 5.09 (2H, s), 6.30 (1H, s), 6.85 (1H,d, J =8.8 Hz), 6.99 (2H, d, J =8.8 Hz), 7.15 (2H, d, J =8.8 Hz),7.34-7.46 (5H, m) , 7.60 (1H, dd, J =2.7 ,8.8 Hz)) , 8.01 (1H, d, J =2.7Hz))

[3138] Example 628

[3139] To a mixture of tert-butyl(2-{4-[1-(4-methoxyphenyl)-3-carboxy-1-H-pyrazol-5-yl]phenoxy}ethyl)carbamate(313.9 mg), piperidine (88.4 mg), and 1-hydroxybenzotriazole (140 mg) inDMF 3 mg was added water soluble carbodiimide hydrochloride (199 mg)under ice-bath cooling. The mixture was stirred at ambient temperatureovernight, then was partitioned between AcOEt and H2O. The organic layerwas separated, washed with 1M HCl, saturated aqueous sodium bicarbonatesolution and saturated aqueous sodium chloride solution, dried overmagnesium sulfate, and concentrated in vacuo. The residue was purifiedby silica gel column chromatography eluted with AcOEt/n-hexane =70%. Theresidu was crystallized from IPE to give tert-butyl2-{4-[1-(4-methoxyphenyl)-3-(1-piperidinyl-carbonyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)carbamate(332.5 mg) as a white powder.

[3140] MS (ESI+) : m/z 521 (M+H)

[3141] 1HNMR (200 MHz, CDCl3): 1.45 (9H, s), 1.53-1.79 (6H, m),3.48-3.57 (2H, m), 3.67-3.81 (2H, m), 3.82 (3H, s), 3.88-4.02 (2H, m),3.98-4.04 (2H, m), 4.96 (1H, brs), 6.77 (1H, s), 6.81 (2H, d, J =8.8Hz), 6.86 (2H, d, J =9.0 Hz), 7.15 (2H, d, J =8.8 Hz), 7.21 (2H, d, J=9.0 Hz)

[3142] The following compound(s) was(were) obtained in a similar mannerto that of Example 628.

[3143] Example 629

[3144] tert-butyl(2-{4-[1-(6-methoxy-3-pyridinyl)-3-(1-piperidinylcarbonyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)-carbamate

[3145] powder

[3146] MS (ESI+) : m/z 522 (M+H)

[3147] 1HNMR (200 MHz, CDCl3): 1.45 (9H, s), 1.54-1.78 (6H, m),3.49-3.57 (2H, m), 3.69-3.82 (2H, m), 3.86-3.99 2H, m), 3.94 (3H, s),3.99-4.05 (2H, m), 4.96 (1H, s), 6.73 (1H, d, J =8.8 Hz), 6.79 (1H, s),6.84 (2H, d, J =8.8 Hz), 7.16 (2H, d, J =8.8 Hz), 7.50 (1H, dd, J =2.7,8.8 Hz), 8.12 (1H, d, J =2.7 Hz)

[3148] Example 630

[3149] tert-butyl(2-{4-[3-t[ethyl(methyl)amino]carbonyl}-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenoxy}-ethyl)carbamate

[3150] powder

[3151] Mass (ESI+) : m/z 496 (M+H)

[3152] 1HNMR (200 MHz, DMSOd6): 1.08-1.22 (3H, m) , 1.37 (9H, s), 2.98,3.29 (3H, s), 3.23-3.32 (2H, m), 3.42-3.53, 3.63-3.75 (2H, m), 3.87 (3H,s), 3.93- 4.00 (2H, m), 6.82, 6.84 (1H, s), 6.87-7.00 (4H, m), 7.21 (2H,d, J =8.6 Hz), 7.61-7.72 (1H, m), 8.13-8.15 (1H, m)

[3153] Example 631

[3154]2-{4-[1-(4-methoxyphenyl)-3-(1-piperidinylcarbonyl)-1-H-pyrazol-5-yl]phenoxy}ethanol

[3155] mp.121.9-123.8° C. Mass (ESI+) : m/z 422 (M+H)

[3156] 1HNMR (200 MHz, DMSOd6) : 1.42-1.74 (6H, m) , 3.53-3.70 (2H, m),3.65-3.73 (2H, m), 3.70-3.92 (2H, m), 3.78 3H, s), 3.95-4.00 (2H, m),4.86 (1H, t, J =5.4 Hz), 6.77 (1H, s), 6.91 (2H, d, J =8.8 Hz), 6.98(2H, d, J =8.9 Hz), 7.16 (2H, d, J =8.8 Hz), 7.23 (2H, d, J =8.9 Hz)

[3157] Example 632

[3158]2-t4-[1-(6-methoxy-3-pyridinyl)-3-(1-piperidinyl-carbonyl)-1-H-pyrazol-5-yl]phenoxy}ethanol

[3159] mp.123.4-124.0° C.

[3160] Mass (ESI+) : m/z 423 (M+H)

[3161] 1HNMR (200 MHz, DMSOd6): 1.45-1.74 (6H, m), 3.50-3.69 (2H, m),3.65-3.74 (2H, m), 3.71-3.90 (2H, m), 3.87 (3H, s), 3.96-4.02 (2H, m),4.86 (1H, t, J =5.4 Hz), 6.81 (1H, s), 6.90 (1H, d, J =8.7 Hz), 6.94(2H, d, J =8.6 Hz), 7.20 (2H, d, J =8.6 Hz), 7.68 (1H, dd, J =2.7 ,8.7Hz), 8.14 (1H, d, J =2.7 Hz)

[3162] Example 633

[3163] tert-butyl{4-[1-(4-methoxyphenyl)-3-(1-piperidinyl-carbonyl)-1-H-pyrazol-5-yl]benzyl}carbamate

[3164] amorphous powderr

[3165] MS (ESI+) : m/z 491 (M+H)

[3166] 1HNMR (200 MHz, CDC13): 1.46 (9H, s), 1.55-1.8 (6H, m), 3.68-3.82(2H, m), 3.82 (3H, s), 3.97-4.00 (2H, m), 4.31 (2H, d, J =6.0 Hz ), 4.84(1H, brs), 6.82 (1H, s), 6.86 (2H, d, J =9 Hz), 7.15-7.25 (6H, m)

[3167] Example 634

[3168] tert-butyl{4-[3-{[ethyl(methyl)amino]carbonyl}-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]benzyl}carbamate

[3169] amorphous powder

[3170] MS (ESI+) : m/z 465 (M+H)

[3171] 1HNMR (200 MHz, CDCl3): 1.20-1.31 (3H, m), 1.46 (9H, s), 3.11,3.40 (3H, s), 3.61, 3.85 (2H, q, J =7.1 Hz), 3.82 (3H, s), 4.31 (2H, d,J =5.8 Hz), 4.86 (1H, brs), 6.81-6.90 (3H, m), 7.16-7.25 (6H, m)

[3172] Example 635

[3173] tert-butyl{4-[3-{[methoxy(methyl)amino]carbonyl}-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]benzyl}carbamate

[3174] solid

[3175] MS (ESI+) : m/z 467 (M+H)

[3176] 1HNMR (200 MHz, CDCl3) : 1.46 (9H, s) , 3.51 (3H, s) , 3.82 (3H,s), 3.85 (3H, s), 4.31 (2H, d, J =5.9 Hz), 4.87 (1H, brs), 6.86 (2H, d,J =9.0 Hz), 6.96 (1H, s), 7.15 -7.26 (6H, m)

[3177] Example 636

[3178] tert-butyl

[3179]{4-[1-(6-methoxy-3-pyridinyl)-3-(1-piperidinyl-carbonyl)-1-H-pyrazol-5-yl]benzyl}carbamate

[3180] oil

[3181] MS (ESI+) : m/z 492 (M+H)

[3182] 1HNMR (200 MHz, DMSOd6): 1.39 (9H, s) , 1.46-1.75 (6H, m),3.52-3.69 (2H, m), 3.75-3.93 (2H, m), 3.87 (3H, s), 4.13 (2H, d, J =6.1Hz), 6.86 (1H, s), 6.90 (1H, d, J=8.9 Hz), 7.19-7.28 (4H, m) , 7.41 (1H,t, J=6.1 Hz) 7.70 (1H, dd, J =2.7 ,8.9 Hz), 8.13 (1H, d, J =2.7 Hz)

[3183] Example 637

[3184] tert-butyl {4-[3-{[ethyl(methyl)amino]carbonyl}-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]benzyl}-carbamate

[3185] oil

[3186] MS (ESI+) : m/z 466 (M+H)

[3187] 1HNMR (200 MHz, DMSOd6): 1.09-1.22 (3H, m), 1.39 (9H, s),2.98,3.28 (3H, s), 3.73-3.77 (2H, m), 3.87 (3H, s), 4.13 (2H, d, J =6.0Hz), 6.87-6.93 (2H, m), 7.18-7.30 (4H, m), 7.41 (1H, t, J =6.0 Hz ),7.65-7.74 (1H, m), 8.14 (1H, d, J =2.6 Hz)

[3188] Example 638

[3189] tert-butyl{4-[3-{[methoxy(methyl)amino]carbonyl}-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]benzyl}carbamate

[3190] powder

[3191] MS (ESI+) : m/z 468 (M+H)

[3192] 1HNMR (200 MHz, DMSOd6): 1.39 (9H, s), 3.37 (3H, s), 3.77 (3H,s), 3.87 (3H, s), 4.13 (2H, d, J =6.1 Hz), 6.91 (1H, d, J =8.8 Hz), 6.97(1H, s), 7.25 (4H, s), 7.42 (1H, t, J =6.1 Hz), 7.71 (1H, dd, J =2.7,8.8 Hz), 8.15 (1H, d, J =2.7 Hz)

[3193] Example 639

[3194]5-[4-(2-hydroxyethyl)phenyl]-N-methoxy-1-(4-methoxy-phenyl)-N-methyl-1-H-pyrazole-3-carboxamide

[3195] oil

[3196] MS (ESI+) : m/z 382 (M+H)

[3197] 1HNMR (200 MHz, CDC13): 1.44 (1H, t, J =5.8 Hz), 2.83-2.90 (2H,m), 3.51 (3H, s), 3.82 (3H, s), 3.85 (3H, s), 3.84-3.89 (2H, m), 6.86(2H, d, J =9.0 Hz), 6.96 (1H, s), 7.13-7.26 (6H, m)

[3198] Example 640

[3199]5-[4-(2-hydroxyethyl)phenyl]-N-methoxy-1-(6-methoxy-3-pyridinyl)-N-methyl-1-H-pyrazole-3-carboxamide

[3200] oil

[3201] Mass (ESI+) : m/z 383 (M+H)

[3202] 1HNMR (200 MHz, CDCl3): 2.84-2.91 (2H, m), 3.51 (3H, s), 3.85(3H, s), 3.81-3.92 (2H, m), 3.95 (3H, s), 6.74 (1H, d, J =8.6 Hz), 6.97(1H, s), 7.20 (4H, s), 7.55 (1H, dd, J =2.8 ,8.6 Hz), 8.13 (1H, d, J=2.8 Hz)

[3203] Example 641

[3204] To a solution oftert-butyl{4-[3-(1-hydroxy-1-methyl-ethyl)-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]benzyl}-carbamate(1.1 g) and Et3N (1.02 g) was added methane sulfonyl chloride (576 mg).The mixture was stirred at ambient temperature overnight. The mixturewas concentrated in vacuo. The residue was partitioned between AcOEt and1M HCl. The organic layer was separated, washed with saturated aqueoussodium bicarbonate solution and saturated aqueous sodium chloridesolution, dried over magnesium sulfate, and concentrated in vacuo. Theresidue was purified by silica gel column chromatography eluted withAcOEt/n-hexane =25%. The pure fraction was collected and concentrated invacuo to give tert-butyl{4-[3-isopropenyl-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]benzyl}carbamate(857 mg) as a solid.

[3205] MS (ESI+) : m/z 420 (M+H)

[3206] 1HNMR (200 MHz, ): 1.46 (9H, s), 2.21 (3H, s), 3.81 (3H, s), 4.30(2H, d, J =5.9 Hz), 4.84 (1H, brs), 5.13 (1H, brs) , 5.60 (1H, brs) ,6.60 (1H, s), 6.84 (2H, d, J=8.9 Hz) 7.18-7.26 (6H, m)

[3207] The following compound(s) was(were) obtained in a similar mannerto that of Example 641.

[3208] Example 642

[3209] tert-butyl{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]benzyl}carbamate

[3210] oil

[3211] MS (ESI+) : m/z 421 (M+H)

[3212] 1HNMR (200 MHz, DMSOd6): 1.39 (9H, s), 2.10 (3H, s), 3.86 (3H,s), 4.12 (2H, d, J =6.2 Hz), 5.15 (1H, brs), 5.63 (1H, brs), 6.88 (1H,s), 6.88 (1H, d, J =8.8 Hz), 7.22 (4H, s), 7.40 (1H, t, J =6.2 Hz), 7.67(1H, dd, J =2.7 , 8.8 Hz), 8.06 (1H, d, J =2.7 Hz)

[3213] Example 643

[3214] A 0.76M solution of isopropyl magnesium bromide in THF (8.5 mg)was added dropwise to a solution of tert-butyl{4-[3-{[methoxy(methyl)amino]carbonyl}-1-(4-methoxy-phenyl)-1-H-pyrazol-5-yl]benzyl}carbamate(1 g) in THF (10 ml) at 10-15° C. The mixture was stirred at ambienttemperature for 4 hours. The reaction mixture was poured into a mixtureof iM HCl and ice. The mixture was extracted with AcOEt. The organiclayer was washed with saturated aqueous sodium bicarbonate solution andsaturated aqueous sodium chloride solution, dried over magnesiumsulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography eluted with AcOEt/n-hexane =20%, 25%, then 10%MeOH/CHCl3. The combined pure fraction was concentrated in vacuo to givetert-butyl{4-[3-isobutyryl-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]benzyl}carbamate(318 mg) as an amorphous powder.

[3215] MS (ESI+) : m/z 450 (M+H)

[3216] 1HNMR (200 MHz, CDCl3) : 1.25 (6H, d, J =6.8 Hz), 1.46 (9H, s),3.72-3.87 (1H, m), 3.83 (3H, s), 4.31 (2H, d, J =5.9 Hz), 4.75-4.93 (1H,m), 6.88 (2H, d, J =9 Hz), 6.98 (1H, s), 7.14-7.27 (6H, m)

[3217] The following compound(s) was (were) obtained in a similar mannerto that of Example 643.

[3218] Example 644

[3219] tert-butyl{4-[3-isobutyryl-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]benzyl}carbamate

[3220] oil

[3221] MS (ESI+) : m/z 451 (M+H)

[3222] 1HNMR (200 MHz, DMSOd6): 1.16 (6H, d, J =6.8 Hz), 1.38 (9H, s),3.68 (1H, m), 3.88 (3H, s), 4.13 (2H, d, J =6.1 Hz), 6.92 (1H, d, J =8.8Hz), 7.07 (1H, s), 7.19-7.29 (4H, m), 7.41 (1H, t, J =6.1 Hz), 7.75 (1H,dd, J =2.7 , 8.8 Hz), 8.17 (1H, d, J =2.7 Hz)

[3223] Example 645

[3224] To a solution of4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoroethoxy)-1-H-pyrazol-5-yl]benzonitrile(197 mg) in THF (2 mg) was added lithium aluminum hydride (30 mg) underice-bath cooling. The mixture was stirred at same temperature for 1 hourand then at ambient temperature for 2 hours. The reaction was quenchedby adding 5% aqueous solution of potassium sodium tartaric acid (ca.0.5mg) . The mixture was diluted with AcOEt, dried over MgSO4, and filteredthrough a celite pad. The filtrate was concentrated in vacuo to give{4-[1-(6-methoxy-3-pyridinyl)-3-(2,2,2-trifluoro-ethoxy)-1-H-pyrazol-5-yl]benzyl}amine(200 mg) as an oil.

[3225] MS ((ESI+) : m/z 379 (M+H)

[3226] 1HNMR (200 MHz, DMSOd6) 3.75 (2H, s), 3.85 (3H, s), 4.84 (1H, d,J =9 Hz), 4.93 (1H, d, J =9 Hz), 6.32 (1H, s), 6.87 (1H, d, J=8.9 Hz),7.19 (2H, d, J =8.2 Hz), 7.33 (2H, d, J =8.2 Hz), 7.64 (1H, dd, J =2.7,8.9 Hz), 8.03 (1H, d, J =2.7 Hz)

[3227] The following compound(s) was(were) obtained in a similar mannerto that of Example 645.

[3228] Example 646

[3229]1-{4-[3-chloro-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]-phenyl}methanamine

[3230] oil

[3231] MS : (ESI+) : m/z 314 (M+H)

[3232] 1HNMR (200 MHz, DMSOd6) : 3.69 (2H, s), 3.78 (3H, s), 6.72 1H,s), 6.96 (2H, d, J =9 Hz), 7.16 (2H, d, J =8.2 Hz), 7.22 (2H, d, J =9Hz), 7.3 (2H, d, J =8.2 Hz)

[3233] Example 647

[3234]1-{4-[3-chloro-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenyl}methanamine

[3235] powder

[3236] MS (ESI+) : m/z 315 (M+H)

[3237] 1HNMR (200 MHz, DMSOd6): 3.70 (2H, s), 3.86 (3H, s), 6.78 (1H,s), 6.89 (1H, d, J =8.7 Hz), 7.20 (2H, d, J =8.3 Hz), 7.33 (2H, d, J=8.3 Hz), 7.69 (1H, dd, J =2.7 ,8.7 Hz), 8.10 (1H, d, J =2.7 Hz)

[3238] Example 648

[3239] A mixture of5-[4-(benzyloxy)phenyl]-3-amino-1-(4-methoxyphenyl)-1-H-pyrazole (4.0g), lithium chloride (2.28 g), and copper(II) chloride (2.90 g) inacetonitrile (50 mg) was stirred at ambient temperature for 10 minutes.To this mixture was added isoamyl nitrite (2.52 g), and the mixture wasstirred at ambient temperature for 1.5 hours. To the reaction mixturewas added a mixture of ethyl acetate and saturated aqueous ammoniumchloride solution. The mixture was stirred at ambient temperature for awhile, and partitioned. The aqueous layer was reextracted with ethylacetate. The combined organic layers were washed with saturated aqueousammonium chloride solution and saturated aqueous sodium chloridesolution, dried over magnesium sulfate, and concentrated in vacuo. Theresidue was purified by silica gel column chromatography eluted with 20%AcOEt/n-hexane. The pure fractions were collected and concentrated invacuo to give5-[4-(benzyloxy)phenyl]-3-chloro-1-(4-methoxyphenyl)-1-H-pyrazole (2.81g) as a solid.

[3240] MS ESI+) : m/z 391 (M+H)

[3241] 1HNMR (200 MHz, CDCl3): 3.81 (3H, s), 5.05 (2H, s), 6.35 (1H, s), 6.84 (2H, d, J 9 Hz), 6.89 (2H, d, J =8.9 Hz), 7.12 (2H, d, J =8.9Hz), 7.19 (2H, d, J =9 Hz), 7.34-7.43 (5H, m)

[3242] Example 649

[3243] A solution of 4-benzyloxypropiophenone (5 g) inN,N-dimethylformamide dimethyl acetal (20 mg) was refluxed for 24 hours.The mixture was concentrated in vacuo. The residue was dissolved intoluene and concentrated in vacuo. This was repeated one more time. Theresidue was dissolved in EtOH. To this solution was added4-methoxyphenylhydrazine hydrochloride (3.63 g), and the mixture wasrefluxed for 3 hours. The reaction mixture was cooled to ambienttemperature and partitioned between AcOEt and 1MHCl. The organic layerwas washed with saturated aqueous sodium bicarbonate solution andsaturated aqueous sodium chloride solution, dried over magnesiumsulfate, and concentrated in vacuo. The residue was purified by silicagel column chromatography eluted with AcOEt/n-hexane =30% to give5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-4-methyl-1-H-pyrazole (5.31g) as a powder.

[3244] MS (ESI+) : m/z 371 (M+H)

[3245] 200 MHz 1HNMR (CDCl3, d) : 2.10 (3H, s), 3.79 (3H, s), 5.06 (2H,s), 6.80 (2H, d, J=8.9 Hz), 6.94 (2H, d, J=8.8 Hz), 7.09 (2H, d, J=8.8Hz), 7.14 (2H, d, J=8.9 Hz), 7.31-7.48 (5H, m), 7.55 (2H, s)

[3246] The following compound(s) was (were) obtained in a similar mannerto that of Example 649.

[3247] Example 650

[3248]5-{5-[4-(benzyloxy)phenyl]-4-methyl-1-H-pyrazol-1-yl}-2-methoxypyridinepowder

[3249] MS (ESI+) : m/z 372 (M+H)

[3250] 200 MHz 1HNMR (CDCl3, d) :2.10 (3H, s), 3.91 (3H, s), 5.06 (2H,s), 6.68 (1H, d, J=8.8 Hz), 6.96 (2H, d, J=8.7 Hz), 7.09 (2H, d, J=8.7Hz), 7.36-7.52 (6H, m), 7.59 (1H, s), 8.02 (1H, d, J=2.7 Hz)

[3251] Example 651

[3252] A solution of t-butyl nitrite (1.14 mg) in CHCl3 (3 mg) was addeddropwise to a solution of5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-3-amino-1-H-pyrazole (1.5 g)and dimethyldisulfide (1.15 mg) in CHCl3 (10 ml). After all of t-butylnitrite solution was added, the tempearature of reaction mixture beganto rise and reached to reflux. After the reflux ceased, the mixture wasstirred at ambient temperature for 1 hour. The mixture was concentratedinvacuo and the residue was purified by silica gel column chromatographyeluted with AcOEt/n-hexane =25% to give5-[4-(benzyloxy)phenyl]-1-(4-methoxyphenyl)-3-(methylthio)-1-H-pyrazole(635.2 mg) as an oil.

[3253] Mass (ESI+) : m/z 403 (M+H)

[3254] 1HNMR (200 MHz, CDCl3): 2.58 (3H, s), 3.81 (3H, s), 5.04 (2H, s),6.36 (1H, s), 6.81-6.91 (4H, m), 7.13 (2H, d, J =8.7 Hz), 7.20 (2H, d, J=9 Hz), 7.34-7.43 (5H, m)

[3255] Example 652

[3256] A mixture of3-cyano-1-(4-methoxyphenyl)-5-[4-(aminometyl)phenyl]-1-H-pyrazole (90mg) trimethylsilylisocyanate (152 mg) and Et3N (0.18 mg) in CH2Cl2 (5ml) was stirred at room temperature. After stirring for 5 hours (checkedby TLC), water and CHCl3 was added. The organic layer was separated.Aqueous layer was extracted with EtOAc. The combined organic layer waswashed with water and brine. Dried over MgSO4, filtered and evaporatedunder reduced pressure to give 48 mg (52%) ofN-{4-[3-cyano-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]benzyl}urea.

[3257] MASS (ESI+): m/z =370.1 (M+Na).

[3258] 1HNMR (200 MHz, CDCl3): 3.83 ( H, s) , 4.38 (2H, d, J =6 Hz) 4.42(2H, b.s), 4.902-(1H, m), 6.82 (1H, s), 6.87 (2H, d, J=9 Hz), 7.15 (2H,d, J =8.3 Hz), 7.19 (2H, d, J =9 Hz), 7.26 (2H, d, J =8.3 Hz) ).

[3259] Example 653

[3260] To a mixture of(2-{4-[3-methoxy-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)aminehydrochloride (150 mg) in CHCl3 (2 mg) and saturated aqueous sodiumbicarbonate solution (1 ml) was added thiophosgene (68.8 mg) underice-bath cooling. The mixture was stirred at ambient temperature for 5hours. To the mixture was added 28% aqueous ammonium hydroxide (1 ml)and the mixture was stirred at ambient temperature overnight. To themixture were added 28% aqueous ammonium hydroxide (1 ml) and MeOH (1 ml)and the mixture was stirred at r. t. for 7 hours. The reaction mixturewas partitioned between AcOEt and H2O. The organic layer was washed withsaturated aqueous sodium bicarbonate solution and saturated aqueoussodium chloride solution, dried over magnesium sulfate, and concentratedin vacuo. The residue was crystallized from ACOEt-IPE. The obtainedpowder was recrystallized from AcOEt-n-hexane to giveN-(2-{4-[3-methoxy-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)thiourea(116 mg) as a powder.

[3261] mp. 141.6-142.3° C.

[3262] MS (ESI+) : m/z 399 (M+H)

[3263] 1HNMR (200 MHz, DMSOd6): 3.61-3.89 (2H, m), 3.75 (3H, s), 3.83(3H, s), 3.98-4.12 (2H, m), 6.04 (1H, s), 6.92 (4H, d, J =8.9 Hz), 7.09(2H, brs), 7.13 (4H, d, J =8.9 Hz), 7.77 (1H, t, J =5.2 Hz)

[3264] Example 654

[3265] A solution of methanesulfonyl chloride (328 mg) in CH2C12 (2 mg)was added to a solution of5-[4-(2-hydroxyethyl)-phenyl]-N-methoxy-1-(4-methoxyphenyl)-N-methyl-1-H-pyrazole-3-carboxamide(840 mg) and Et3N (334 mg) in CH2C12 (10 ml) under ice bath cooling. Themixture was stirred at same temperature for 1 hour. The mixture wasdiluted with CDCl3 and washed with 1M HCl, saturated aqueous sodiumbicarbonate solution and saturated aqueous sodium chloride solution,dried over magnesium sulfate, and concentrated in vacuo. The residue waspurified by silica gel column chromatography eluted with AcOEt/n-hexane=80%, 90%. The pure fractions were collected and concentrated in vacuoto give 2-{4-[3-{[methoxy(methyl)amino]carbonyl}-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenyl}ethyl methanesulfonate (1.01 g) as an oil.

[3266] Mass (ESI+) : m/z 460 (M+H)

[3267] 1HNMR (200 MHz, CDC13): 2.89 (3H, s), 3.05 (2H, t, J =6.8 Hz),3.51 (3H, s), 3.83 (3H, s), 3.85 (3H, s), 4.41 2H, t, J =6.8 Hz), 6.86(2H, d, J =9.0 Hz), 6.97 (1H, s), 7.18-7.26 (6H, m)

[3268] The following compound(s) was(were) obtained in a similar mannerto that of Example 654.

[3269] Example 655

[3270]2-{4-[3-{[methoxy(methyl)amino]carbonyl}-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenyl}ethyl

[3271] methanesulfonate

[3272] oil

[3273] Mass (ESI+) : m/z 461 (M+H)

[3274] 1HNMR (200 MHz, CDC13): 2.91 (3H, s), 3.06 (2H, t, J =6.8 Hz),3.50 (3H, s), 3.85 (3H, s), 3.94 (3H, s), 4.43 (2H, t, J =6.8 Hz), 6.74(1H, d, J =8.8 Hz), 6.99 (1H, s), 7.32 (4H, s), 7.55 (1H, dd, J =2.7,8.8 Hz), 8.09 (1H, d, J =2.7 Hz)

[3275] Example 656

[3276] A mixture of2-{4-[3-{[methoxy(methyl)amino]-carbonyl}-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenyl}ethylmethanesulfonate (1.02 g), 15-crown-5 (489 mg), sodium azide (722 mg) inhexamethylphosphoric triamide (6 mg) was stirred at 55° C. for 1hour.The mixture was poured into ice water, and the mixture was extractedwith AcOEt. The organic layer was washed with saturated aqueous sodiumchloride solution, dried over magnesium sulfate, and concentrated invacuo. The residue was dissolved in MeOH (6 mg). To this solution wasadded a solution of 6M HCl (0.37 mg) in MeOH (2 mg) and 10% palladium oncarbon (50%wet) (200 mg). The mixture was hydrogenated under H2 latm atambient temperature for 2 hours. The catalyst was removed by filtration.The filtrate was concentrated in vacuo to give5-[4-(2-aminoethyl)phenyl]-N-methoxy-1-(4-methoxy-phenyl)-N-methyl-1-H-pyrazole-3-carboxamidehydrochloride (0.93 g) as an oil.

[3277] Mass (ESI+) : m/z 381 (M+H)

[3278] 1HNMR (200 MHz, DMSOd6): 2.79-3.16 (4H, m), 3.38 (3H, s), 3.77(3H, s), 3.79 (3H, s), 6.95 (1H, s), 6.99 (2H, d, J =9.0 Hz), 7.15-7.36(6H, m), 8.00 (2H, brs)

[3279] The following compound(s) was (were) obtained in a similar mannerto that of Example 656.

[3280] Example 657

[3281]5-[4-(2-aminoethyl)phenyl]-N-methoxy-1-(6-methoxy-3-pyridinyl)-N-methyl-1-H-pyrazole-3-carboxamide

[3282] hydrochloride

[3283] oil

[3284] Mass (ESI+) : m/z 382 (M+H)

[3285] 1HNMR (200 MHz, DMSOd6): 2.80-3.15 (4H, m), 3.38 (3H, s) , 3.77(3H, s), 3.88 (3H, s) , 6.92 (1H, d, J =8.8 Hz), 6.98 (1H, s), 7.22-7.36(4H, m), 7.72 (1H, dd, J=2.7 ,8.8 Hz), 8.02 (2H, brs), 8.17 (1H, d, J=2.7 Hz)

[3286] Example 658

[3287] To a 0.76M solution of isopropylmagnesium bromide in THF (2.0 ml)was added a solution of5-(4-{2-[(aminocarbonyl)-amino]ethyl}phenyl)-N-methoxy-1-(4-methoxyphenyl)-N-methyl-1-H-pyrazole-3-carboxamide(130 mg) in THF (2 mg) dropwise at at 4° C. The mixture was stirred atambient temperature overnight. Additional 0.76M solution ofisopropylmagnesium bromide in THF (2.) ml) was added and the mixture wasstirred at 50° C. for 5 hours. The reaction mixture was cooled toambient temperature and was quenched by adding saturated aqueousammonium chloride solution. The mixture was extracted with AcOEt. Theoreganic layer was washed with 1M HCl, saturated aqueous sodiumbicarbonate solution, saturated aqueous sodium chloride solution, driedover magnesium sulfate, and concentrated in vacuo. The residue waspurified by preparative thin layer silica gel chromatography developedby MeOH/CHC3 10%. The seaparated silica gel was extracted with 10%MeOH/CHCl3 and the solvent was evaporated in vacuo to giveN-(2-{4-[3-isobutyryl-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenyl}ethyl)urea(30 mg) as amorphous powder.

[3288] MS (ESI+) : m/z 407 (M+H)

[3289] 1HNMR (200 MHz, CDCl3): 1.25 (6H, d, J =6.8 Hz), 2.77 -2.85 (2H,m), 3.37-3.48 (2H, m), 3.72-3.87 (1H, m), 3.83 (3H, s), 4.32 (2H, s),4.57 (1H, t, J =4.9 Hz), 6.89 (2H, d, J =8.9 Hz), 6.96 (1H, s), 7.14(4H, s), 7.24 (2H, d, J =8.9 Hz)

[3290] The following compound(s) was (were) obtained in a similar mannerto that of Example 658.

[3291] Example 659

[3292]N-(2-{4-[3-isobutyryl-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenyl}ethyl)methanesulfonamide

[3293] oil

[3294] MS (ESI+) : m/z 442

[3295]1HNMR (200 MHz, CDCl3): 1.26 (6H, d, J =6.9 Hz), 2.84-2.91 (2H,m), 2.87 (3H, s), 3.35-3.46 (2H, m), 3.73-3.87 (1H, m), 3.84 (3H, s),4.21 (1H, t, J =6.1 Hz), 6.89 (2H, d, J =9.0 Hz), 6.99 (1H, s),7.13-7.29 (6H, m)

[3296] Example 660

[3297]N-(2-{4-[3-isobutyryl-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenyl}ethyl)urea

[3298] oil

[3299] MS (ESI+) : m/z 408 (M+H)

[3300] 1HNMR (200 MHz, CDC13) : 1.26 (6H, d, J =6.9 Hz), 2.79-2.87 (2H,m), 3.39-3.50 (2H, m), 3.77- (1H, m), 3.95 (3H, s), 4.35 (2H, s), 4.57(1H, t, J =5.4 Hz), 6.78 (1H, d, J =8.9 Hz), 6.98 (1H, s), 7.17 (4H, s),7.60 (1H, dd, J =2.7 ,8.9 Hz), 8.07 (1H, d, J =2.7 Hz)

[3301] Example 661

[3302]N-(2-{4-[3-isobutyryl-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenyl}ethyl)methanesulfonamide

[3303] oil

[3304] MS (ESI+) : m/z 443 (M+H)

[3305] 1HNMR (200 MHz, CDCl3): 1.26 (6H, d, J =6.8 Hz), 2.85-2.93 (2H,m), 2.88 (3H, s), 3.36-3.47 (2H, m), 3.77 (3H, m), 3.95 (3H, s), 4.24(1H, t, J =6.2 Hz), 6.78 (1H, d, J =8.8 Hz), 7.00 (1H, s), 7.19 (4H, s),7.57 (1H, dd, J =2.7 ,8.8 Hz), 8.11 (1H, d, J =2.7 Hz)

[3306] Example 662

[3307] To a solution of cyclopropylmagnesium bromide, which was preparedfrom cyclopropyl bromide (257 mg) and magnesium (57 mg) in THF (1 ml) asusual method, was added a solution of5-(4-{2-[(aminocarbonyl)-amino]ethyl}phenyl)-N-methoxy-1-(4-methoxyphenyl)-N-methyl-1-H-pyrazole-3-carboxamide(90 mg) in THF (3 mg) dropwise at ambient temperature. The mixture wasstirred at 50° C. for 5 hours. The reaction mixture was cooled toambient temperature and was quenched by adding saturated aqueousammonium chloride solution. The mixture was extracted with AcOEt. Theoreganic layer was washed with 1M HCl, saturated aqueous sodiumbicarbonate solution, saturated aqueous sodium chloride solution, driedover magnesium sulfate, and concentrated in vacuo. The residue waspurified by preparative thin layer silica gel chromatography developedby MeOH/CHC3 10%. The seaparated silica gel was extracted with 10%MeOH/CHCl3 and the solvent was evaporated in vacuo to giveN-(2-{4-[3-(cyclopropylcarbonyl)-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenyl}ethyl)urea(23 mg) as a powder.

[3308] Mass (ESI+) : m/z 405 (M+H)

[3309] 1HNMR (200 MHz, CDCl3): 0.99-1.09 (2H, m), 1.22-1.30 (2H, m),2.77-2.84 (2H, m), 3.13 (1H, m), 3.37-3.48 (2H, m), 3.84 (3H, s), 4.33(2H, s), 4.59 (1H, t, J =5.4 Hz), 6.89 (2H, d, J =8.9 Hz), 6.96 (1H, s),7.14 (4H, s), 7.26 (2H, d, J =8.9 Hz)

[3310] The following compound(s) was(were) obtained in a similar mannerto that of Example 662.

[3311] Example 663

[3312]N-(2-{4-[3-(cyclopropylcarbonyl)-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenyl}ethyl)methanesulfonamide

[3313] oil

[3314] MS (ESI+) : m/z 440 (M+H

[3315] 1HNMR (200 MHz, CDCl3): 0.99-1.09 (2H, m), 1.22-1.31 (2H, m),2.80-2.91 (2H, m), 2.87 (3H, s), 3.14 (1H, m), 3.35-3.46 (2H, m), 3.84(1H, s), 4.22 (1H, t, J =5.7 Hz), 6.90 (2H, d, J =9.0 Hz), 6.99 (1H, s),7.12 4H, s), 7.27 (2H, d, J =9.0 Hz)

[3316] Example 664

[3317]N-(2-(4-[3-(cyclopropylcarbonyl)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenyl}ethyl)methane-sulfonamide

[3318] oil

[3319] Mass (ESI+) : m/z 441 (M+H)

[3320] 1HNMR (200 MHz, CDC13): 1.03-1.11 (2H, m), 1.24-1.32 2H, m),2.85-2.93 (2H, m), 2.88 (3H, s), .3.11 (1H, m), 3.36-3.47 (2H, m), 3.96(3H, s), 4.22 ( IH, t, J =6.0 Hz), 6.78 (1H, d, J =8.9 Hz), 7.00 ( IH,s), 7.20 4H, s), 7.60 (1H, dd, J =2.7 ,8.9 Hz), 8.13 (1H, d, J =2.7 Hz)

1. A compound of the formula (I):

wherein R¹ is hydrogen or lower alkyl; R² is lower alkyl optionallysubstituted with halogen, hydroxy, lower alkoxyimino or lower alkoxy;lower alkenyl; cycloalkyl; cyano; lower alkanoyl; cycloalkylcarbonyl;N,N-di(lower)alkylcarbamoyl; carbamoyl; N-lower alkoxy-N-loweralkylcarbamoyl; amino; di(lower)alkylamino; lower alkoxycarbonylamino;N,N-di(lower)alkylcarbamoylamino;N-(N,N-di(lower)alkylcarbamoyl)-N-lower alkylamino; halogen; hydroxy;carboxy; lower alkoxycarbonyl; aroyl; heterocycliccarbonyl; heterocyclicgroup; lower alkylsulfonyl; lower alkoxy optionally substituted withlower alkoxy, N,N-di(lower)alkylcarbamoyl or halogen; cycloalkyloxy;lower alkylthio; or lower alkylsufinyl; R³is lower alkyl optionallysubstituted with amino, carbamoylamino or lower alkylsulfonylamino;halogen; cyano; hydroxy; lower alkanoyloxy; lower alkylenedioxy; loweralkoxy optionally substituted with aryl, hydroxy, cyano, amino, loweralkoxycarbonylamino, lower alkylsulfonylamino or carbamoylamino; nitro;amino; hetrocyclic group; lower alkylthio; lower alkylsulfinyl; or loweralkylsufonyl; R⁴is hydrogen; cyano; amino optionally substituted withphthaloyl or lower alkyl; aryl; heterocyclic group; lower alkoxy;hydroxy; lower alkylsulfonyloxy; lower alkanoyloxy; lower alkylsubstituted with tritylamino and lower alkoxycarbonyl, amino and loweralkoxycarbonyl, amino and carboxy, amino and carbamoyl, or amino andhydroxy; N-lower alkoxycarbonyl-N-lower alkylamino; lower alkanoyloptionally substituted with halogen; carboxy; lower alkylsulfonyl;sulfo; lower alkylsilyloxy; lower alkoxycarbonyl; sulfamoyl optionallysubstituted with lower alkyl; carbamoyl optionally substituted withlower alkyl; lower alkylthio; lower alkylsulfinyl; carbamoyloxy;thioureido; or a group of the formula: R⁵ -G-J- in which G is -CO- or-SO₂-; J is -N(R⁶)- (wherein R⁶ is hydrogen or lower alkyl); and R⁵ isamino optionally substituted with lower alkoxycarbonyl or lower alkyl;lower alkyl optionally substituted with hydroxy, loweralkoxycarbonylamino, lower alkanoyloxy, amino or halogen; lower alkoxy;hydrogen; heterocyclic group; or aryl; X is 0, S, SO or SO_(2;) Y is CHor N; Z is lower alkylene or lower alkenylene; and m is 0 or 1; providedthat when R⁴ is hydrogen; then R³ is lower alkyl substituted with amino,carbamoylamino or lower alkylsulfonylamino; or lower alkoxy substitutedwith aryl, hydroxy, cyano, amino, lower alkoxycarbonylamino, loweralkylsulfonylamino or carbamoylamino; or salts thereof.
 2. The compoundof claim 1, wherein R³ is hydrogen; R²is lower alkyl optionallysubstituted with halogen, hydroxy, lower alkyoxyimino or lower alkoxy;cycloalkyl; halogen; lower alkoxy optionally substituted with halogen;or lower alkylthio; R³ is lower alkoxy optionally substituted with aryl,hydroxy, cyano, amino, lower alkoxyxcarbonylamino, loweralkylsulfonylamino or carbamoylamino; R⁴ is a group of the formula: R⁵-G-J- in which R^(5,) G and J are each as defined in claim 1; X is O orS; and Z is lower alkylene.
 3. The compound of claim 2, wherein R²islower alkyl optionally substituted with halogen; cycloalkyl; halogen; orlower alkoxy optionally substituted with halogen; R³ is lower alkoxy; R⁴is a group of the formula: R⁵-G-J- in which G is -CO- or -SO₂-, J is-NH- and R⁵ is amino or lower alkyl; and X is O.
 4. The compound ofclaim 3, which isN-(2-{4-[3-chloro-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]-phenoxy}ethyl)urea,N-(4-[3-(difluoromethyl)-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]benzyl}methanesulfonamide,N-{4-[3-(difluoromethyl)-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]benzyl}urea,N-(2-{4-[3-(difluoromethyl)-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)urea,N-(2-{4-[l-(4-methoxyphenyl)-3-(trifluoromethyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)urea,N-(2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)urea,N-(2-{4-[3-cyclopropyl-1-(4-methoxyphenyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)urea,N-(2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)urea,N-(2-{4-[1-(4-methoxyphenyl)-3-(trifluoromethyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)acetamide,orN-(2-{4-[3-(2,2-difluoroethoxy)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenoxy}ethyl)urea.5. A process of preparing a compound of the formula:

wherein R¹ is hydrogen or lower alkyl; R² is lower alkyl optionallysubstituted with halogen, hydroxy, lower alkoxyimino or lower alkoxy;lower alkenyl; cycloalkyl; cyano; lower alkanoyl; cycloalkylcarbonyl;N,N-di(lower)alkylcarbamoyl; carbamoyl; N-lower alkoxy-N-loweralkylcarbamoyl; amino; di(lower)alkylamino; lower alkoxycarbonylamino;N,N-di(lower)alkylcarbamoylamino;N-(N,N-di(lower)alkylcarbamoyl)-N-lower alkylamino; halogen; hydroxy;carboxy; lower alkoxycarbonyl; aroyl; heterocycliccarbonyl; heterocyclicgroup; lower alkylsulfonyl; lower alkoxy optionally substituted withlower alkoxy, N,N-di(lower)alkylcarbamoyl or halogen; cycloalkyloxy;lower alkylthio; or lower alkylsufinyl; R³ is lower alkyl optionallysubstituted with amino, carbamoylamino or lower alkylsulfonylamino;halogen; cyano; hydroxy; lower alkanoyloxy; lower alkylenedioxy; loweralkoxy optionally substituted with aryl, hydroxy, cyano, amino, loweralkoxycarbonylamino, lower alkylsulfonylamino or carbamoylamino; nitro;amino; hetrocyclic group; lower alkylthio; lower alkylsulfinyl; or loweralkylsufonyl; R⁴ is hydrogen; cyano; amino optionally substituted withphthaloyl or lower alkyl; aryl; heterocyclic group; lower alkoxy;hydroxy; lower alkylsulfonyloxy; lower alkanoyloxy; lower alkylsubstituted with tritylamino and lower alkoxycarbonyl, amino and loweralkoxycarbonyl, amino and carboxy, amino and carbamoyl, or amino andhydroxy; N-lower alkoxycarbonyl-N-lower alkylamino; lower alkanoyloptionally substituted with halogen; carboxy; lower alkylsulfonyl;sulfo; lower alkylsilyloxy; lower alkoxycarbonyl; sulfamoyl optionallysubstituted with lower alkyl; carbamoyl optionally substituted withlower alkyl; lower alkylthio; lower alkylsulfinyl; carbamoyloxy;thioureido; or a group of the formula: R⁵ -G-J- in which G is -CO- or-SO₂-; J is -N(R⁶)- (wherein R⁶ is hydrogen or lower alkyl) ; and R⁵isamino optionally substituted with lower alkoxycarbonyl or lower alkyl;lower alkyl optionally substituted with hydroxy, loweralkoxycarbonylamino, lower alkanoyloxy, amino or halogen; lower alkoxy;hydrogen; heterocyclic group; or aryl; X is O, S, SO or SO₂; Y is CH orN; Z is lower alkylene or lower alkenylene; and m is O or 1; providedthat when R⁴ is hydrogen; then R³ is lower alkyl substituted with amino,carbamoylamino or lower alkylsulfonylamino; or lower alkoxy substitutedwith aryl, hydroxy, cyano, amino, lower alkoxycarbonylamino, loweralkylsulfonylamino or carbamoylamino; or salts thereof, whichcomprises, 1) reacting a compound of the formula:

or its salt with a compound of the formula:

or its salt in the acidic condition to provide a compound of theformula:

or its salt, in the above formulas, R′, R^(2,) R^(3,) R′, X, Y, Z and mare each as defined above, or 2) reacting a compound of the formula:

or its salt with a compound (V) of the formula: R⁴—Z—Q  (V) or its saltto provide a compound of the formula:

or its salt, in the above formulas: R¹, R², R³, R⁴, Y and Z are eachdefined above, Xa is O or S, and Q is hydroxy or an acid residue.
 6. Apharmaceutical composition comprising the compound of claim 1, as anactive ingredient, in association with a pharmaceutically non-toxiccarrier or excipient.
 7. A compound of claim 1 for use as a medicament8. A method for treatment and/or prevention of inflammatory conditions,various pains, collagen diseases, autoimmune diseases, various immunitydiseases, analgesic, thrombosis, cancer or neurodegerative diseaseswhich comprises administering an effective amount of the compound ofclaim 1 to human beings or animals.
 9. Use of the compound of claim 1for the manufacture of a medicament for treatment and/or prevention ofinflammatoryconditions, various pains, collagendiseases, autoimmunediseases, various immunity diseases, analgesic, thrombosis, cancer orneurodegerative diseases in human beings or animals.
 10. The analgesicagent comprising the compound of claim 1, which is usable for treatingand/or preventing pains caused by or associated with acute or chronicinflammations without causing gastrointestinal disorders.
 11. Theanalgesic agent of claim 10, which is usable for treating or preventingpains caused by or associated with rheumatoid arthritis, osteoarthritis,lumbar rheumatism, rheumatoid spondylitis, gouty arthritis, or juvenilearthritis; lumbago; cervico-omo-brachial syndrome; scapulohumeralperiarthritis; pain and tumescence after operation or injury withoutcausing gastrointestinal disorders.
 12. A commercial package comprisingthe pharmaceutical composition containing the compound (I) identified inclaim 1 and a written matter associated therewith, wherein the writtenmatter states that the compound (I) can or should be used for preventingor treating inflammatory conditions, various pains, collagen diseases,autoimmune diseases, various immunity diseases, analgesic, thrombosis,cancer or neurodegerative diseases.